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MX2008006882A - Noncompetitive domain antibody formats that bind interleukin 1 receptor type 1 - Google Patents

Noncompetitive domain antibody formats that bind interleukin 1 receptor type 1

Info

Publication number
MX2008006882A
MX2008006882A MXMX/A/2008/006882A MX2008006882A MX2008006882A MX 2008006882 A MX2008006882 A MX 2008006882A MX 2008006882 A MX2008006882 A MX 2008006882A MX 2008006882 A MX2008006882 A MX 2008006882A
Authority
MX
Mexico
Prior art keywords
seq
dom4
tar2h
dom7r
dab
Prior art date
Application number
MXMX/A/2008/006882A
Other languages
Spanish (es)
Inventor
M Tomlinson Ian
Basran Amrik
D Drew Philip
M T De Wildt Rudolf
Original Assignee
Basran Amrik
De Wildt Rudolf Mt
Domantis Limited
D Drew Philip
M Tomlinson Ian
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Basran Amrik, De Wildt Rudolf Mt, Domantis Limited, D Drew Philip, M Tomlinson Ian filed Critical Basran Amrik
Publication of MX2008006882A publication Critical patent/MX2008006882A/en

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Abstract

The invention relates to dAb monomers that bind IL-1R1 and inhibit binding of IL- 1 (e.g. , IL- 1αand/or IL- 1β) to the receptor but do not inhibit binding of IL- 1 ra to IL- 1R1, and to ligands comprising such dAb monomers. The invention relates to protease resistand dAb monomers, and to ligands comprising protease resistant dAb monomers. The invention also relates to nucleic acids including vectors that encode the dAb monomers and ligand, to host cells that comprise the nucleic acids and to method for producing a dAb monomer or ligand. The invention also relates to pharmaceutical compositions that comprise the dAb monomers or ligands, and to therapeutic methods that comprise administering a dAb monomer of ligand.

Description

NON-COMPETITIVE DOMAIN ANTIBODY FORMATS THAT ARE LINKED TO THE INTERLEUCINE-1 TYPE-1 RECEIVER RELATED APPLICATION This application claims the benefit of the Provisional Application of the United States of America Number 60 / 742,062, filed on December 1, 2005. All the teachings of the previous application are incorporated herein by reference. BACKGROUND OF THE INVENTION? nterleuc? na-1 (IL-1) is an important mediator of the immune response that has biological effects on several cell types. Interleukin-1 binds to two receptors, the interleukin-1 type 1 receptor (IL-1R1, CD121A, p80), which transduces the signal into cells after binding with IL-1 , and Interleukin-1 receptor type 2 (IL-1R1, CDw121b), which does not transduce signals after binding with IL-1, and acts as an endogenous regulator of IL-1. Another endogenous protein that regulates the interaction of IL-1 with IL-1R1 is the antagonist of the heterosteric na-1 receptor (IL-1 ra) I L-1 ra binds to IL-1R1, but does not activate the I L-1 R 1 for transduce the signals. The signals transduced through IL-1R1 after binding with IL-1 (for example, IL-1a or I L-1β) induce a broad spectrum of biological activities that can be pathogenic. By example, the signals transduced through I L-1 R 1 after IL-1 binding, can lead to local or systemic inflammation, to the elaboration of additional inflammatory mediators (for example, I L-6, IL-8, TNF), fever, activation of immune cells (eg, lymphocytes, neutrophils), anorexia, hypotension, leukopenia, and thrombocytopenia Signals transduced through IL-1R1 after IL-1 binding also have effects on the non-immune cells, such as the stimulation of chondrocytes to release collagenase and other enzymes that degrade the cartilage, and the stimulation of the differentiation of osteoclast progenitor cells into mature osteoclasts, which leads to bone resorption (See, for example, Hallegua and Weisman, Ann Theum Dis 6V960-967 (2002)) In accordance with the above, the interaction of IL-1 with I L-1 R 1 has been implicated in the pathogenesis of several diseases, such as arthritis ( for example , rheumatoid arthritis, osteoartptis), and inflammatory bowel disease Certain agents that bind to the Interleukin-1 Receptor Type 1 (IL-1R1), and that neutralize its activity (eg, I L-1 ra) have proven to be effective therapeutic agents for certain inflammatory conditions, such as moderately to severely active rheumatoid arthritis. However, other agents that bind to IL-1R1, such as the anti? -IL-1 R 1 AMG 108 (Amgen) antibody, have failed to reach the primary endpoints in clinical studies There is a need for better agents that antagonize IL-1R1, and methods to administer these agents for the disease. BRIEF DESCRIPTION OF THE INVENTION The invention relates to domain antibody monomers (dAb) that bind to IL-1R1, and that inhibit the binding of IL-1 (e.g., IL-1a and / or IL-1β) with the receptor, but do not inhibit the binding of IL-1ra with IL-1R1, and ligands comprising these dAb monomers. These ligands and monomers of dAb are useful as therapeutic agents for the treatment of inflammation, disease, or other conditions mediated in whole or in part by the biological functions induced by the binding of IL-1 with IL-1R1 (eg, local inflammation). or systemic, elaboration of inflammatory mediators (for example, I L-6, IL-8, TNF), fever, activation of immune cells (for example, lymphocytes, neutrophils), anorexia, hypotension, leukopenia, thrombocytopenia). The dAb ligands or monomers of the invention can bind to IL-1R1, and inhibit the function of IL-1R1, without interfering with the endogenous IL-1R1 inhibitory pathways, such as the binding of endogenous IL-1ra with the IL -1R1 endogenous. Accordingly, this ligand or dAb monomer can be administered to a subject to complement the endogenous regulatory pathways that inhibit the activity of IL-1R1 or IL-1 in vivo. In addition, ligands or monomers of dAb that bind to IL-1R1 and that do not inhibit the binding of I L-1 ra with IL-1R1, provide advantages for use as diagnostic agents, because they can be used for link and detect, quantify or measure IL-1R1 in a sample, and will not compete with I L-1 ra in the sample by binding with IL-1R1 According to the above, an accurate determination can be made of whether there is IL-1R1 and how much in the sample The monomers of dAb that bind to I L-1 R 1 and that inhibit the binding of IL-1 (for example, IL-1a and / or I L-1β) to the receptor , but they do not inhibit the binding of IL-1ra with IL-1R1, they are also useful as research tools. For example, this dAb monomer can be used to identify agents (eg, other dAbs, small organic molecules) that bind to IL-1R1, but not inhibiting the binding of IL-1ra to IL-1R1 In an illustrative example, an agent or a collection of agents to be tested is tested for their ability to inhibit IL-1 binding with IL-1R1, in a competitive IL-1R1 receptor binding assay, such as the receptor binding assay described in the present Then we can study the agents that inhibit the binding of IL-1 with IL-1R1 in this assay, in a similar competitive IL-1R1 receptor binding assay, to see if they compete with a dAb monomer that binds to IL-1R1 but does not inhibit the binding of IL-1ra with I L-1 R 1 The competitive binding in this assay indicates that the agent binds to IL-1R1 and that it inhibits the binding of IL-1 with the receptor, but which does not inhibit the binding of I L-1 ra to the receptor. In one aspect, the invention relates to a monomer of (dAb) that has binding specificity for the receptor of ? nterleuc? na-1 type 1 (IL-1R1), and which inhibits the binding of interleukin-1 (IL-1, for example? nterleuc? na-1 to (IL-1 a) and / or? terleucine -1β (IL-1ß)) with the receptor, but which does not inhibit the binding of the interferon-1 receptor antagonist (IL-1ra) with IL-1R1. Preferably, the dAb monomer inhibits the binding of IL-1 with IL-1R1 with an IC50 which is < 1 μM. In some embodiments, the monomer of dAb inhibits the IL-1-induced release of nterleucin-8 from the MRC-5 cells (ATCC Accession Number CCL-171) in a m vitro assay, with an ND50 that is < 1 μM, or preferably < 1 nM In other embodiments, the dAb monomer inhibits the IL-1-induced release of the nterleuclease na-6 in a whole blood assay, with an ND50 which is < 1 μM In other embodiments, the dAb monomer inhibits the IL-1-induced release of the nterleuclease na-6 in a whole blood assay, with an ND50 which is < 1 μM. One or more of the structure regions (FR) in the dAb monomer may comprise (a) the amino acid sequence of a region of human structure, (b) at least 8 contiguous amino acids of the amino acid sequence of a region of human structure, or (c) an amino acid sequence encoded by a genetic segment of the human germ line antibody, wherein these structure regions are as defined by Kabat. The amino acid sequences of one or more structure regions in the dAb monomer may be the same as amino acid sequence of a region of corresponding structure encoded by a genetic segment of human germline antibody, or the amino acid sequences of one or more of the structure regions collectively comprise up to five amino acid differences relative to the structure regions corresponding ones encoded by a genetic segment of human germline antibody The amino acid sequences of FR1, FR2, FR3, and FR4 in the dAb monomer, can be the same as the amino acid sequences of the corresponding structure regions encoded by a segment of the human germline antibody, or the amino acid sequences of FR1, FR2, FR3, and FR4 collectively contain up to 10 amino acid differences relative to the corresponding structure regions encoded by a genetic segment of the human germline antibody The dAb monomer may comprise FR1 regions, FR2, and FR3, and the amino acid sequence of these FR1, FR2, and FR3 may be the same as the amino acid sequences of the corresponding structure regions encoded by a genetic segment of the human germline antibody. In some embodiments, the Genetic segment of human germline antibody is DPK9 and JK1 In some embodiments, the dAb monomer competes for the linkage with IL-1R1 with a dAb selected from the group that consists of DOM4-122-23 (SEQ ID NO: 1), DOM4-122-24 (SEQ ID NO: 2), DOM4-122 (SEQ ID NO: 95), DOM4-122-1 (SEQ ID NO: 96) ), DOM4-122-2 (SEQ ID NO: 97), DOM4-122-3 (SEQ ID NO: 98), DOM4-122-4 (SEQ ID NO: 99), DOM4-122-5 (SEQ ID NO. : 100), DOM4-122-6 (SEQ ID NO: 101), DOM4-122-7 (SEQ ID NO: 102), DOM4-122-8 (SEQ ID NO: 103), DOM4-122-9 (SEQ ID NO: 104), DOM4-122-10 (SEQ ID NO: 105) DOM4-122-11 (SEQ ID NO: 106 DOM4-122-12 (SEQ ID NO: 107) DOM4-122-13 (SEQ ID NO: 108 DOM4-122-14 (SEQ ID NO: 109) DOM4- 122-15 (SEQ ID NO: -110 DOM4-122-16 (SEQ ID NO: 111) DOM4-122-17 (SEQ ID NO.112 DOM4-122-18 (SEQ ID NO: 113) DOM4- 122 - 19 (SEQ ID NO 114 DOM4- 122-20 (SEQ ID NO: 115) DOM4- 122-21 (SEQ ID NO 116 DOM4- 122-22 (SEQ ID NO: 117) DOM4- 122-25 (SEQ ID NO. 118 DOM4-122-26 (SEQ ID NO: 119) DOM4-122-27 (SEQ ID NO 120 DOM4-122-28 (SEQ ID NO: 121) DOM4-12229 (SEQ ID NO 122 DOM4- 122-30) (SEQ. ID NO: 123) DOM4-122-31 (SEQ ID NO 124 DOM4-122-32 (SEQ ID NO: 125) DOM4 122-33 (SEQ ID NO 126 DOM4- 122 • 34 (SEQ ID NO: 127) DOM4 - 122 -35 (SEQ ID NO 128 DOM4- 122 -36 (SEQ ID NO: 129) DOM4 -122 -37 (SEQ ID NO 130 DOM4- 122 -38 (SEQ ID NO: 131) DOM4 -122 -39 (SEQ ID NO 132 DOM4- 122 -40 (SEQ ID NO: 133) DOM4 -122 -41 (SEQ ID NO 134 DOM4 -122 -42 (SEQ ID NO: 135) DOM4 -122 -43 (SEQ ID NO 136 DOM4 -122 - 44 (SEQ ID NO: 137) DOM4 -122 -45 (SEQ ID NO 138 DOM4 -122 -46 (S EQ ID NO: 139) DOM4 -122 -47 (SEQ ID NO 140 DOM4 -122 -48 (SEQ ID NO: 141) DOM4 -122 -49 (SEQ ID NO 142 DOM4 -122 -50 (SEQ ID NO: 143 DOM4-122-51 (SEQ ID NO: 144) DOM4-122-52 (SEQ ID NO: 145 DOM4-122-54 (SEQ ID NO: 146) DOM4-122-55 (SEQ ID NO: 147 DOM4 -122-56 (SEQ ID NO: 148) DOM4-122-57 (SEQ ID NO: 149 DOM4-122-58 (SEQ ID NO: 150) DOM4-122-59 (SEQ ID NO: 151 DOM4-122-60 (SEQ ID NO: 152) DOM4-122-61 (SEQ ID NO: 153 DOM4-122-62 (SEQ ID NO: 154) DOM4-122-63 (SEQ ID NO: 155 DOM4-122-64 (SEQ ID NO. : 156) DOM4-122-65 (SEQ ID NO: 157 DOM4-122-66 (SEQ ID NO: 158) DOM4-122-67 (SEQ ID NO: 159 DOM4-122-68 (SEQ ID NO: 160) DOM4 -122-69 (SEQ ID NO: 161 DOM4-122-70 (SEQ ID NO: 162) DOM4-122-71 (SEQ ID NO: 163 DOM4-122-72 (SEQ ID NO: 164) DOM4-122-73 (SEQ ID NO: 165 DOM4-1 (SEQ ID NO: 8), DOM4-2 (SEQ ID NO: 9), DOM4-3 (SEQ ID NO: 10), DOM4-4 (SEQ ID NO: 11), DOM4-5 (SEQ ID NO: 12), DOM4-6 (SEQ ID NO: 13), DOM4-7 (SEQ ID NO: 14), DOM4-8 (SEQ ID NO: 15), DOM4-9 (SEQ ID NO: 16), DOM4-10 (SEQ ID NO: 17), DOM4-11 (SEQ ID NO: 18), DOM4-12 (SEQ ID NO: 19), DOM4-13 (SEQ ID NO: 20), DOM4 -14 (SEQ ID NO: 21), DOM4-15 (SEQ ID NO: 22), DOM4-20 (SEQ ID NO: 23), DOM4-21 (SEQ ID NO: 24), DOM4-22 (SEQ ID NO: 25), DOM4-23 (SEQ ID NO: 26), DOM4-25 (SEQ ID NO: 27), DOM4-26 (SEQ ID NO: 28), DOM4 -27 (SEQ ID NO: 29), DOM4-28 (SEQ ID NO: 30), DOM4-29 (SEQ ID NO: 31), DOM4-31 (SEQ ID NO: 32), DOM4-32 (SEQ ID NO. : 33), DOM4-33 (SEQ ID NO: 34), DOM4-34 (SEQ ID NO: 35), DOM4-36 (SEQ ID NO: 36), DOM4-37 (SEQ ID NO: 37), DOM4- 38 (SEQ ID NO: 38), DOM4-39 (SEQ ID NO: 39), DOM4-40 (SEQ ID NO: 40), DOM4-41 (SEQ ID NO: 41), DOM4-42 (SEQ ID NO: 42), DOM4-44 (SEQ ID NO: 43), DOM4-45 (SEQ ID NO: 44), DOM4-46 (SEQ ID NO: 45), DOM4 -49 (SEQ ID NO: 46), DOM4-50 (SEQ ID NO: 47), DOM4-74 (SEQ ID NO: 48), DOM4-75 (SEQ ID NO: 49), DOM4-76 (SEQ ID NO. : 50), DOM4-78 (SEQ ID NO: 51), DOM4-79 (SEQ ID NO: 52), DOM4-80 (SEQ ID NO: 53), DOM4-81 (SEQ ID NO: 54), DOM4-82 (SEQ ID NO: 55), DOM4-83 (SEQ ID NO: 56), DOM4-84 (SEQ ID NO: 57 ), DOM4-85 (SEQ ID NO: 58), DOM4-86 (SEQ ID NO: 59), DOM4-87 (SEQ ID NO: 60), DOM4-88 (SEQ ID NO: 61), DOM4-89 ( SEQ ID NO: 62), DOM4-90 (SEQ ID NO: 63), DOM4-91 (SEQ ID NO: 64), DOM4-92 (SEQ ID NO: 65), DOM4-93 (SEQ ID NO: 66), DOM4-94 (SEQ ID NO: 67), DOM4-95 (SEQ ID NO: 68), DOM4-96 (SEQ ID NO: 69), DOM4-97 (SEQ ID NO: 70), DOM4-98 (SEQ ID NO: 71), DOM4-99 (SEQ ID NO: 72), DOM4-100 (SEQ ID NO: 73), DOM4 -101 (SEQ ID NO: 74), DOM4-102 (SEQ ID NO: 75), DOM4-103 (SEQ ID NO: 76), DOM4-104 (SEQ ID NO: 77), DOM4-105 (SEQ ID NO. : 78), DOM4-106 (SEQ ID NO: 79), DOM4-107 (SEQ ID NO: 80), DOM4-108 (SEQ ID NO: 81), DOM4-109 (SEQ ID NO: 82), DOM4- 110 (SEQ ID NO: 83), DOM4-111 (SEQ ID NO: 84), DOM4-112 (SEQ ID NO: 85), DOM4-113 (SEQ ID NO: 86), DOM4-114 (SEQ ID NO: 87), DOM4-115 (SEQ ID NO: 88), DOM4-116 (SEQ ID NO: 89), DOM4-117 (SEQ ID NO: 90), DOM4-118 (SEQ ID NO: 91), DOM4-119 (SEQ ID NO: 92 ), DOM4-120 (SEQ ID NO: 93), DOM4-121 (SEQ ID NO: 94), DOM4-123 (SEQ ID NO: 166), DOM4-124 (SEQ ID NO: 167) DOM4-125 (SEQ ID NO: 168), DOM4-126 (SEQ ID NO: 169), DOM4-127 (SEQ ID NO: 170), DOM4-128 (SEQ ID NO: 171), DOM4-129 (SEQ ID NO: 172), DOM4-129-1 (SEQ ID NO: 173,) DOM4-129-2 (SEQ ID NO: 174), DOM4- 129-3 (SEQ ID NO: 175), DOM4-129-4 (SEQ ID NO: 176), DOM4-129-5 (SEQ ID NO: 77), DOM4-129-6 (SEQ ID NO: 178), DOM4-129-7 (SEQ ID NO: 179 DOM4-129-8 (SEQ ID NO: 180 DOM4-129-9 (SEQ ID NO: 181 DOM4- 129-10 SEQ ID NO: 182 DOM4-129-11 (SEQ ID NO: 183 DOM4- 129- 12 SEQ ID NO: 184 DOM4-129-13 (SEQ ID NO: 185 DOM4- 129- 14 SEQ ID NO: 186 DOM4-129-15 (SEQ ID NO: 187 DOM4- 129- 16 SEQ ID NO: 188 DOM4-129-17 (SEQ ID NO: 189 DOM4- 129- 18 SEQ ID NO: 190 DOM4-129-19 (SEQ ID NO: 191 DOM4- 129-20 SEQ ID NO: 192 DOM4-129-21 (SEQ ID NO: 193 DOM4- 129- 22 SEQ ID NO: 194 DOM4-129-23 (SEQ ID NO: 195 DOM4- 129- 24 SEQ ID NO: 196 DOM4-129-25 (SEQ ID NO: 197 DOM4- 129 26 SEQ ID NO: 198 DOM4-129-27 (SEQ ID NO: 199 DOM4- 129 28 SEQ ID NO: 200 DOM4-129-29 (SEQ ID NO: 201 DOM4- 129 -31 SEQ ID NO: 202 DOM4-129-32 (SEQ ID NO: 203 DOM4 129 -33 SEQ ID NO: 204 DOM4-129-34 (SEQ ID NO: 205 DOM4 -129 -35 SEQ ID NO: 206 DOM4-129-37 (SEQ ID NO: 207 DOM4 -129 -38 SEQ ID NO: 208 DOM4-129-39 (SEQ ID NO: 209 DOM4 -129 -40 SEQ ID NO: 210 DOM4-129-41 (SEQ ID NO: 211 DOM4 -129 -42 SEQ ID NO: 212) DOM4-129-43 (SEQ ID NO: 213 DOM4-129-44 (SEQ ID NO: 214), DOM4-131 (SEQ ID NO: 347 DOM4-132 (SEQ ID NO: 348), and DOM4-133 (SEQ ID NO: 349 Preferably, the dAb monomer competes for the link to IL-1R1, with a dAb selected from the group consisting of DOM4-122-23 (SEQ ID NO: 1), DOM4-122-24 (SEQ ID NO: 2), DOM4-122 (SEQ ID NO: 95), DOM4-122-1 (SEQ ID NO: 96), DOM4-122-2 (SEQ ID NO: 97), DOM4-122-3 (SEQ ID NO: 98), DOM4-122-4 (SEQ ID NO: 99), DOM4-122-5 (SEQ ID NO: 100), DOM4-122-6 (SEQ ID NO: 101), DOM4-122-7 (SEQ ID NO: 102), DOM4-122-8 (SEQ ID NO: 103), DOM4-122-9 (SEQ ID NO: 104), DOM4-122 -10 (SEQ ID NO: 105), DOM4-122-11 (SEQ ID NO: 106), DOM4-122-12 (SEQ ID NO: 107), DOM4-122-13 (SEQ ID NO: 108), DOM4 -122-14 (SEQ ID NO: 109), DOM4-122-15 (SEQ ID NO: 110), DOM4-122-16 (SEQ ID NO: 111), DOM4-122-17 (SEQ ID NO: 112), DOM4-122-18 (SEQ ID NO: 1 13), DOM4-122-19 (SEQ ID NO: 114), DOM4-122-20 (SEQ ID NO: 115), DOM4-122-21 (SEQ ID NO: 116), DOM4-122-22 (SEQ ID NO: 117), DOM4-122-25 (SEQ ID NO: 118), DOM4-122 -26 (SEQ ID NO: 119), DOM4-122-27 (SEQ ID NO: 120), DOM4-122-28 (SEQ ID NO: 121), DOM4-122-29 (SEQ ID NO: 122), DOM4-122-30 (SEQ ID NO: 123), DOM4-122-31 (SEQ ID NO: 124), DOM4-122-32 ( SEQ ID NO: 125), DOM4-122-33 (SEQ ID NO: 126), DOM4-122-34 (SEQ ID NO: 127), DOM4-122-35 (SEQ ID NO: 128), DOM4-122- 36 (SEQ ID NO: 129), DOM4-122-37 (SEQ ID NO: 130), DOM4-122-38 (SEQ ID NO: 131), DOM4-122-39 (SEQ ID NO: 132), DOM4-122-40 (SEQ ID NO: 133), DOM4-122-41 (SEQ ID NO: 134), DOM4-122-42 ( SEQ ID NO: 135), DOM4-122-43 (SEQ ID NO: 136), DOM4-122-44 (SEQ ID NO: -137), DOM4-122-45 (SEQ ID NO: 138), DOM4-122 -46 (SEQ ID NO: 139), DOM4-122-47 (SEQ ID NO: 140), DOM4-122-48 (SEQ ID NO 141) DOM4-122-49 (SEQ ID NO 142) DOM4-122-50 (SEQ ID NO 143) DOM4-122-51 (SEQ ID NO 144) DOM4-122-52 (SEQ ID NO 145) DOM4-122 -54 (SEQ ID NO 146) DOM4-122-55 (SEQ ID NO 147) DOM4-122-56 (SEQ ID NO 148) DOM4-122-57 (SEQ ID NO 149) DOM4-122-58 (SEQ ID NO. 150) DOM4-122-59 (SEQ ID NO 151) DOM4-122-60 (SEQ ID NO 152) DOM4-122-61 (SEQ ID NO 153) DOM4-122-62 (SEQ ID NO 154) DOM4-122- 63 (SEQ ID NO 155) DOM4-122-64 (SEQ ID NO 156) DOM4-122-65 (SEQ ID NO 157) DOM4-122-66 (SEQ ID NO 158) DOM4-122-67 (SEQ ID NO 159) ) DOM4-122-68 (SEQ ID NO 160) DOM4-122-69 (SEQ ID NO 161) DOM4-122-70 (SEQ ID NO 162) DOM4-122-71 (SEQ ID NO 163) DOM4-122-72 (SEQ ID NO 164), and DOM4-122-73 (SEQ ID NO 165) In other embodiments, the dAb monomer comprises an amino acid sequence having an amino acid sequence identity of at least about 90 percent with the amino acid sequence of a dAb selected from the group consisting of DOM4-122-23 (SEQ ID NO 1), DOM4-122-24 (SEQ ID NO 2), DOM4-122 (SEQ ID NO 95), DOM4-122-1 (SEQ ID NO 96), DOM4-122-2 (SEQ ID NO 97), DOM4-122 -3 (SEQ ID NO 98), DOM4-122-4 (SEQ ID NO 99), DOM4-122-5 (SEQ ID NO 100), DOM4-122-6 (SEQ ID NO 101), DOM4-122-7 (SEQ ID NO 102), DOM4-122-8 (SEQ ID NO 103), DOM4-122-9 (SEQ ID NO 104), DOM4-122-10 (SEQ ID NO 105), DOM4-122-11 (SEQ. ID NO 106), DOM4-122-12 (SEQ ID NO 107), DOM4-122-13 (SEQ ID NO 108), DOM4-122-14 (SEQ ID NO: 109), DOM4-122-15 (SEQ ID NO: 110), DOM4- 122-16 (SEQ ID NO: 111) DOM4-122-17 (SEQ ID NO112), DOM4- 122-18 (SEQ ID NO: 113), DOM4-122-19 (SEQ ID NO: 114), DOM4- 122-20 (SEQ ID NO: 115), DOM4-122-21 (SEQ ID NO: 116), DOM4- 122-22 (SEQ ID NO: 117), DOM4-122-25 (SEQ ID NO: 118), DOM4- 122-26 (SEQ ID NO: 119), DOM4-122-27 (SEQ ID NO: 120), DOM4- 122-28 (SEQ ID NO: 121), DOM4-122-29 (SEQ ID NO: 122), DO 4- 122-30 (SEQ ID NO: 123), DOM4-122-31 (SEQ ID NO: 124), DOM4- 122-32 (SEQ ID NO: 125), DOM4-122-33 (SEQ ID NO 126), DOM4- 122-34 (SEQ ID NO: 127), DOM4-122-35 (SEQ ID NO 128), DOM4- 122-36 (SEQ ID NO: 129), DOM4-122-37 (SEQ ID NO 130), DOM4- 122-38 (SEQ ID NO: 131), DOM4-122-39 (SEQ ID NO132), DOM4- 122-40 (SEQ ID NO: 133), DOM4-122-41 (SEQ ID NO 134), DOM4- 122-42 (SEQ ID NO: 135), DOM4-122-43 SEQ ID NO 136), DOM4- 122-44 (SEQ ID NO: 137), DOM4-122-45 SEQ ID NO 138), DOM4- 122-46 (SEQ ID NO: 139), DOM4-122-47 SEQ ID NO 140), DOM4- 122-48 (SEQ ID NO: 141), DOM4-122-49 SEQ ID NO 142), DOM4- 122-50 (SEQ ID NO: 143), DOM4-122-51 [SEQ ID NO 144), DOM4 -122-52 (SEQ ID NO: 145), DOM4-122-54 (SEQ ID NO 146), DOM4 -122-55 (SEQ ID NO: 147), DOM4-122-56 (SEQ ID NO 148), DOM4 -122-57 (SEQ ID NO: 149), DOM4-122-58 (SEQ ID NO 150), DOM4 -122-59 (SEQ ID NO: 151), DOM4-122-60 (SEQ ID NO 152), DOM4 -122-61 (SEQ ID NO: 153), DOM4-122-62 (SEQ ID NO .154), DOM4 -122-63 (SEQ ID NO: 155), DOM4-122-64 (SEQ ID NO: 156), DOM4 -122-65 (SEQ ID NO: 157), DOM4-122-66 (SEQ ID NO: 158), DOM4 -122-67 (SEQ ID NO: 159), DOM4-122-68 (SEQ ID NO: 160), DOM4-122-69 (SEQ ID NO: 161), DOM4-122-70 (SEQ ID NO: 162), DOM4-122 -71 (SEQ ID NO: 163), DOM4-122-72 (SEQ ID NO: 164), DOM4-122-73 (SEQ ID NO: 165), DOM4-1 (SEQ ID NO: 8), DOM4-2 (SEQ ID NO: 9), DOM4-3 (SEQ ID NO: 10), DOM4-4 (SEQ ID NO: 11), DOM4-5 (SEQ ID NO: 12), DOM4-6 (SEQ ID NO: 13), DOM4-7 (SEQ ID NO: 14), DOM4-8 (SEQ ID NO: 15), DOM4-9 (SEQ ID NO: 16), DOM4 -10 (SEQ ID NO: 17), DOM4-11 (SEQ ID NO: 18), DOM4-12 (SEQ ID NO: 19), DOM4-13 (SEQ ID NO: 20), DOM4-14 (SEQ ID NO. : 21), DOM4-15 (SEQ ID NO: 22), DOM4-20 (SEQ ID NO: 23), DOM4-21 (SEQ ID NO: 24), DOM4-22 (SEQ ID NO: 25), DOM4-23 (SEQ ID NO: 26), DOM4-25 (SEQ ID NO: 27), DOM4-26 (SEQ ID NO: 28), DOM4 -27 (SEQ ID NO: 29), DOM4-28 (SEQ ID NO: 30), DOM4-29 (SEQ ID NO: 31), DOM4-31 (SEQ ID NO: 32), DOM4-32 (SEQ ID NO. : 33), DOM4-33 (SEQ ID NO: 34), DOM4-34 (SEQ ID NO: 35), DOM4-36 (SEQ ID NO: 36), 'DOM4-37 (SEQ ID NO: 37), DOM4-38 (SEQ ID NO: 38), DOM4-39 (SEQ ID NO: 39), DOM4-40 (SEQ ID NO: 40), DOM4-41 (SEQ ID NO: 41), DOM4-42 (SEQ ID NO: 42), DOM4-44 (SEQ ID NO: 43), DOM4-45 (SEQ ID NO: 44), DOM4-46 (SEQ ID NO: 45), DOM4-49 (SEQ ID NO: 46), DOM4-50 (SEQ ID NO: 47), DOM4-74 (SEQ ID NO: 48), DOM4-75 (SEQ ID NO: 49), DOM4-76 (SEQ ID NO: 50), DOM4-78 (SEQ ID NO: 51), DOM4-79 (SEQ ID NO: 52), DOM4-80 (SEQ ID NO: 53), DOM4-81 (SEQ ID NO: 54), DOM4-82 (SEQ ID NO: 55), DOM4-83 (SEQ ID NO: 56), DOM4 -84 (SEQ ID NO: 57), DOM4-85 (SEQ ID NO: 58), DOM4-86 (SEQ ID NO: 59), DOM4-87 (SEQ ID NO: 60), DOM4-88 (SEQ ID NO: 61), DOM4-89 (SEQ ID NO: 62), DOM4-90 (SEQ ID NO: 63), DOM4 -91 (SEQ ID NO: 64), DOM4-92 (SEQ ID NO: 65), DOM4-93 (SEQ ID NO: 66), DOM4-94 (SEQ ID NO: 67), DOM4-95 (SEQ ID NO. : 68), DOM4-96 (SEQ ID NO: 69), DOM4-97 (SEQ ID NO: 70), DOM4-98 (SEQ ID NO: 71), DOM4-99 (SEQ ID NO: 72), DOM4-100 (SEQ ID NO: 73), DOM4-101 (SEQ ID NO: 74), DOM4-102 (SEQ ID NO: 75) ), DOM4-103 (SEQ ID NO: 76), DOM4-104 (SEQ ID NO: 77), DOM4-105 (SEQ ID NO: 78), DOM4-106 (SEQ ID NO: 79), DOM4-107 ( SEQ ID NO: 80), DOM4-108 (SEQ ID NO: 81), DOM4-109 (SEQ ID NO: 82), DOM4-110 (SEQ ID NO: 83), DOM4-111 (SEQ ID NO: 84), DOM4-112 (SEQ ID NO: 85), DOM4-113 (SEQ ID NO: 86), DOM4-114 (SEQ ID NO: 87), DOM4-115 (SEQ ID NO: 88), DOM4-116 (SEQ ID NO: 89), DOM4-117 (SEQ ID NO: 90), DOM4-118 (SEQ ID NO: 91), DOM4 -119 (SEQ ID NO: 92), DOM4-120 (SEQ ID NO: 93), DOM4-121 (SEQ ID NO: 94), DOM4-123 (SEQ ID NO: 166), DOM4-124 (SEQ ID NO: 167) DOM4-125 (SEQ ID NO: 168), DOM4-126 (SEQ ID NO: 169), DOM4- 127 (SEQ ID NO: 170), DOM4-128 (SEQ ID NO: 171), DOM4-129 (SEQ ID NO: 172), DOM4-129-1 (SEQ ID NO: 173,) DOM4-129-2 ( SEQ ID NO: 174), DOM4-129-3 (SEQ ID NO: 175), DOM4-129-4 (SEQ ID NO: 176), DOM4-129-5 (SEQ ID NO: 177), DOM4-129-6 (SEQ ID NO: 178), DOM4-129-7 (SEQ ID NO: 179), DOM4-129-8 ( SEQ ID NO: 180), DOM4-129-9 (SEQ ID NO: 181), DOM4-129-10 (SEQ ID NO: 182), DOM4-129-11 (SEQ ID NO: 183), DOM4-129- 12 (SEQ ID NO: 184), DOM4-129-13 (SEQ ID NO: 185), DOM4-129-14 (SEQ ID NO: 186 DOM4- 129- 15 SEQ ID NO: 187 DOM4- 129 16 (SEQ ID NO: 188 DOM4- 129- 17 SEQ ID NO: 189 DOM4- 129 • 18 (SEQ ID NO: 190 DOM4- 129-19 SEQ ID NO: 191 DOM4- 129 20 (SEQ ID NO: 192 DOM4- 129-21 SEQ ID NO: 193 DOM4- 129 22 (SEQ ID NO: 194 DOM4- 129-23 SEQ ID NO: 195 DOM4- 129 24 (SEQ ID NO: 196 DOM4- 129- 25 SEQ ID NO: 197 DOM4- 129 • 26 (SEQ ID NO: 198 DOM4- 129- 27 SEQ ID NO: 199 DOM4- 129 • 28 (SEQ ID NO: 200 DOM4- 129- 29 SEQ ID NO: 201 DOM4-129 • 31 (SEQ ID NO: 202 DOM4- 129 32 SEQ ID NO: 203 DOM4- 129 • 33 (SEQ ID NO: 204 DOM4- 129 34 SEQ ID NO: 205 DOM4- 129 • 35 (SEQ ID NO: 206 DOM4- 129-37 SEQ ID NO: 207 DOM4- 129 • 38 (SEQ ID NO: 208 DOM4 129-39 SEQ ID NO: 209 DOM4 129-40 (SEQ ID NO: 210 DOM4 -129 -41 SEQ ID NO: 211 DOM4 • 129 -42 (SEQ ID NO: 212 DOM4 -129 -43 SEQ ID NO: 213) DOM4 -129 -44 (SEQ ID NO: 214 DOM4-131 (SEQ ID NO: 347) , DOM4-132 (SEQ ID NO: 348), and DOM4-133 (SEQ ID NO: 349) Preferably, the dAb monomer comprises an amino acid sequence having an identity of amino acid sequence of at least about 90 percent with an amino acid sequence selected from the group consisting of DOM4-122-23 (SEQ ID NO: 1), DOM4-122-24 (SEQ ID NO: 2), DOM4-122 (SEQ ID NO: 95), DOM4-122-1 (SEQ ID NO: 96), DOM4-122-2 (SEQ ID NO: 97), DOM4-122-3 (SEQ ID NO: 98), DOM4-122-4 (SEQ ID NO: 99), DOM4-122-5 (SEQ ID NO: 100), DOM4-122-6 (SEQ ID NO: 101), DOM4-122-7 (SEQ ID NO: 102) ), DOM4-122-8 (SEQ ID NO: 103), DOM4-122-9 (SEQ ID NO: 104) DOM4-122-10 (SEQ ID NO: 105), DOM4-122-11 (SEQ ID NO: 106 DOM4-122-12 (SEQ ID NO: 107), DOM4-122-13 (SEQ ID NO: 108 DOM4-122-14 (SEQ ID NO: 109), DOM4-122-15 (SEQ ID NO: -110 DOM4-122-16 (SEQ ID NO: 111), DOM4-122-17 (SEQ ID NO: 112 DOM4-122-18 (SEQ ID NO: 113), DOM4-122-19 (SEQ ID NO: 114 DOM4-122-20 (SEQ ID NO: 115), DOM4-122-21 (SEQ ID NO: 116 DOM4-122-22 (SEQ ID NO: 117), DOM4-122-25 (SEQ ID NO: 118 DOM4-122-26 (SEQ ID NO: 119), DOM4-122-27 (SEQ ID NO: 120 DOM4-122-28 (SEQ ID NO: 121), DOM4-122-29 (SEQ ID NO: 122 DOM4-122-30 (SEQ ID NO: 123), DOM4-122-31 (SEQ ID NO: 124 DOM4-122-32 (SEQ ID NO: 125), DOM4-122-33 (SEQ ID NO: 126 DOM4-122-34 (SEQ ID NO: 127), DOM4-122-35 (SEQ ID NO: 128 DOM4-122-36 (SEQ ID NO: 129), DOM4-122-37 (SEQ ID NO: 130 DOM4-122-38 (SEQ ID NO: 131), DOM4-122-39 (SEQ ID NO: 132 DOM4-122-40 (SEQ ID NO: 133), DOM4-122-41 (SEQ ID NO: 134 DOM4-122-42 (SEQ ID NO: 135), DOM4-122-43 (SEQ ID NO: 136 DOM4-122-44 (SEQ ID NO: 137), DOM4-122-45 (SEQ ID NO: 138 DOM4-122-46 (SEQ ID NO: 139), DOM4-122-47 (SEQ ID NO: 140 DOM4-122-48 (SEQ ID NO: 141), DOM4-122-49 (SEQ ID NO-.142 DOM4-122-50 (SEQ ID NO: 143), DOM4-122-51 (SEQ ID NO: 144 DOM4-122-52 (SEQ ID NO: 145), DOM4-122-54 (SEQ ID NO: 146 DOM4-122-55 (SEQ ID NO: 147), DOM4-122-56 (SEQ ID NO: 148 DOM4-122-57 (SEQ ID NO: 149), DOM4-122-58 (SEQ ID NO: 150 DOM4-122-59 (SEQ ID NO: 151), DOM4-122-60 (SEQ ID NO: 152 DOM4-122-61 (SEQ ID NO: 153), DOM4-122-62 (SEQ ID NO: 154), DOM4-122-63 (SEQ ID NO: 155), DOM4-122-64 (SEQ ID NO: 156), DOM4-122-65 ( SEQ ID NO: 157), DOM4-122-66 (SEQ ID NO: 158), DOM4-122-67 (SEQ ID NO: 159), DOM4-122-68 (SEQ ID NO: 160), DOM4-122- 69 (SEQ ID NO: 161), DOM4-122-70 (SEQ ID NO: 162), DOM4-122-71 (SEQ ID NO: 163), DOM4-122-72 (SEQ ID NO: 164), and DOM4-122-73 (SEQ ID NO: 165). Preferably, the dAb monomer binds to human IL-1R1 with an affinity (KD) of about 300 nM to about 5 pM, as determined by surface plasmon resonance. In another aspect, the invention relates to a ligand comprising a dAb monomer that has binding specificity for the interleukin-1 type 1 receptor (IL-1R1), and which inhibits the binding of interleukin-1 (IL-1). , for example interleukin-1 a (IL-1a) and / or interleukin-lß (I-1 ß)) with the receptor, but that does not inhibit the binding of Interleukin-1 Receptor Antagonist (iL-1 ra) with IL-1R1, and a fraction that prolongs half-life. The fraction that prolongs the half-life can be a polyalkylene glycol fraction, serum albumin or a fragment thereof, the transferrin receptor or a transferrin binding portion thereof, or an antibody or antibody fragment comprising a site of linkage for a polypeptide that improves the half-life in vivo. In some situations, the fraction that prolongs the half-life is an antibody or an antibody fragment that comprises a binding site for serum albumin or neonatal Fe receptor In particular embodiments, the fraction that prolongs half-life is a single immunoglobulin variable domain that competes with an anti-serum albumin dAb disclosed herein, by linking to human serum albumin In other particular embodiments, the fraction that prolongs the half-life is a single variable domain of immunoglobulin comprising an amino acid sequence having an amino acid sequence identity of at least 90 percent with the amino acid sequence of the anti-serum albumin dAb disclosed herein In the most particular embodiments, the invention is a ligand comprising a dAb monomer having binding specificity for IL-1R1, and which inhibits the binding of IL-1 with the receptor, but does not inhibit the binding of IL-1 ra with IL-1R1, where this dAb monomer is selected from the group consisting of DOM4-122-23 and DOM4-122-24. igando may be, for example, a dAb monomer, or a homodimer, homotrimer, or homo-oligomer of this dAb monomer. The ligand may further comprise a dAb monomer that binds to serum albumin, such as DOM7h-8. . For example, in some embodiments, the ligand comprises DOM4-122-23 and DOM7h-8, or comprises DOM-122-24 and DOM7h-8 In other particular embodiments, the invention is a ligand comprising a dAb monomer having specificity of binding to IL-1R1, and inhibits the binding of IL-1 to the receptor, but does not inhibit the binding of I L-1 ra with IL-1R1, and a dAb monomer having binding specificity for the receptor of the tumor necrosis factor 1 (TNFR1). If desired, the ligand may further comprise a moiety that extends the half-life. Preferably, the dAb monomer having binding specificity for TNFR1, competes for binding to TNFR1 with a dAb ant? -TNFR1 described herein In some embodiments, the dAb monomer having binding specificity for TNFR1, comprises an amino acid sequence having an amino acid sequence identity of at least about 90 percent with an amino acid sequence of an anti-TNFR1 dAb described herein The invention also relates to an isolated or recombinant nucleic acid encoding a dAb monomer or a ligand, and to vectors (e.g., expression vectors) comprising the recombinant nucleic acid. The invention also relates to a host cell comprising a recombinant nucleic acid or a vector, and to a method for producing a dAb ligand or monomer, which comprises maintaining a host cell of the invention under conditions suitable for the expression of the acid Nucleic encoding a dAb ligand or monomer of the invention The invention also relates to pharmaceutical compositions comprising a dAb monomer or a ligand, and a physiologically acceptable carrier. For example, a composition for intravenous, intramuscular, mtrapeptoneal, mtra-artepal, intrathecal, intra-articular, subcutaneous, pulmonary, intranasal, vaginal, or rectal administration The invention also relates to a drug delivery device comprising the pharmaceutical composition of the invention. example, the drug delivery device can be a parenteral delivery device, an intravenous delivery device, an intramuscular delivery device, an intrapeptoneal delivery device, a transdermal delivery device, a pulmonary delivery device, a delivery device mtra-artepal, an intrathecal delivery device, an intra-articular delivery device, a subcutaneous delivery device, an intranasal delivery device, a vaginal delivery device, or a rectal delivery device. Examples of these delivery devices include a syringe, a transdermal delivery device (e.g., a patch), a capsule, a tablet, a nebulizer, an inhaler, an atomizer, an aerosolizer, a fine mist nebulizer, a dry powder inhaler, a metered dose inhaler, a metered dose sprayer, a nebulizer Measured dose, a metered dose sprayer, and a catheter The invention also relates to a method for the treatment of an inflammatory disease, which comprises administering to a subject in need, a therapeutically effective amount of a dAb monomer or a ligand of the invention. The invention also relates to a dAb monomer or ligand of the invention, for use in therapy, diagnosis, and / or prophylaxis, and to the use of a dAb monomer or ligand of the invention for the manufacture of a medicament for the treatment of a disease described herein (eg, an inflammatory disease, arthritis, a respiratory disease) The invention also relates to a method for the treatment of a disease (eg, an inflammatory disease, arthritis, a respiratory disease), which comprises administering to a subject in need thereof, a therapeutically effective amount of a dAb monomer that is resistant to degradation by the protease. The invention also relates to a dAb monomer that is resistant to degradation by the protease, used in therapy, diagnosis, or prophylaxis, and the use of this dAb monomer of the invention for the manufacture of a medicament for the treatment of of a disease described herein (for example, an inflammatory disease, arthritis, a respiratory disease). BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the results of an in vitro assay, where the dAbs were tested for their ability to inhibit the IL-1 release induced by IL-1 from MRC-cells. 5 cultured (ATCC, Catalog Number CCL-171) Figure 1 shows a dose response curve for dAbs anti-IL-1R 1, referred to as DOM4-122 and DOM4-129 in this cellular assay The ND50 values of both dAbs were approximately 1 μM Figure 2 is a graph showing the results of the m vitro assays, where dAbs that underwent affinity maturation were tested for their ability to inhibit the IL-1-induced IL-1 release from cultured MRC-5 cells (ATCC, Catalog Number CCL-171) Figure 2 shows a dose response curve for DOM4-122-6, DOM4-129-1, DOM4-122-23, and IL-1ra DOM4-122-6 and DOM4-122-23 are variants matured by affinity of DOM- 4-122, and DOM4-129-1 is an affinity-matured variant of DOM4-129. Both DOM4-122-6 and DOM4-129-1 had an ND50 of approximately 10 nM in the assay, and DOM4-122-23 had an ND50 of approximately 1 nM in the assay Figures 3A and 3B are sensograms showing that DOM4-122-23 (Figure 3A) but not IL-1 a (Figure 3B) bound to IL-1R1, with which it was alreadylinked I L- 1 ra I L- 1 ra was injected over the immobilized IL-1R1, and bound to the immobilized receptor (Injection 1, from 0 to 60 seconds in Figures 3A and 3B) Then, either DOM4 was injected -122-23 or IL-1a (Injection 2, 60 to 120 seconds in Figures 3A and 3B) As seen in the sensorgrams, DOM4-122-23 bound to IL-1R1 with which it had already bound I L- 1 ra, but I L- 1 to no Figure 4 is a graph showing that Increasing concentrations of DOM4-122-23 did not inhibit the binding of IL-1ra with I L-1 R 1 in a competitive binding ELISA, but that IL-1a inhibited the binding of I L-1 ra with IL-1R1 in the assay Increasing concentrations of DOM-4-122-23 or IL-1a were mixed with 500 pM IL-1ra, and the mixture was applied to an ELISA plate which was coated with IL-1 R1 Figures 5A through 5Z illustrate the amino acid sequences of several human dAbs that bind to the human I L-1 R 1. In some of the sequences, the amino acids of the CDR1, CDR2, and CDR3 are underlined Figures 6A to 6Z, 6AA to 6ZZ, 6AAA and 6BBB illustrate the nucleotide sequences of the nucleic acids encoding the human dAbs shown in Figures 5A -5Z In some of the sequences, the nucleotides encoding CDR1, CDR2, and CDR3 are underlined. Figure 7A is an alignment of the amino acid sequences of three VKS selected by binding to mouse serum albumin (MSA). aligned amino acid sequences are from the VKS designated as MSA16, which is also referred to as DOM7m-16 (SEQ ID NO 723), MSA-12, which is also referred to as DOM7m-12 (SEQ ID NO: 724), and MSA-26, which is also referred to as DOM7m-26 (SEQ ID NO-725) Figure 7B is an alignment of the amino acid sequences of six VKS selected by the link with rat serum albumin (RCA) amino acid sequences aligned are from the VKS designated as DOM7r-1 (SEQ ID NO 726), DOM7r-3 (SEQ ID NO'727), DOM7r-4 (SEQ ID NO: 728), DOM7r-5 (SEQ ID NO 729) , DOM7r-7 (SEQ ID NO: 730), and DOM7r-8 (SEQ ID NO 731) Figure 7C is an alignment of the amino acid sequences of six VKS selected by binding to human serum albumin (HSA). The aligned amino acid sequences are from the VKS designated as DOM7h-2 (SEQ ID NO 732), DOM7h-3 (SEQ ID NO 733), DOM7h-4 (SEQ ID NO: 734), DOM7h-6 (SEQ ID N0735), DOM7h-1 (SEQ ID NO: 736), and DOM7h-7 (SEQ ID NO: 737) Figure 7D is an alignment of the amino acid sequences of seven VHs selected by binding to human serum albumin, and a sequence in consensus (SEQ ID NO-738). The aligned sequences are from the VHs designated as DOM7h-22 (SEQ ID NO.739), DOM7h-23 (SEQ ID NO-740), DOM7h-24 (SEQ ID NO: 741), DOM7h-25 (SEQ ID N0742), DOM7h-26 (SEQ ID NO: 743), DOM7h-21 (SEQ ID NO 744), and DOM7h-27 (SEQ ID NO'745). Figure 7E is an alignment of the amino acid sequences of three VKS selected by binding to human serum albumin and rat serum albumin. The aligned amino acid sequences are from the VKS designated as DOM7h-8 (SEQ ID NO-746), DOM7r-13 (SEQ ID NO: 747), and DOM7r-14 (SEQ ID NO: 748) Figure 8 is an illustration of the amino acid sequences of the VKS selected by the rat serum albumin (RSA) linkage. The illustrated sequences are from the VKS designated as DOM7r-15 (SEQ ID NO: 749), DOM7r-16 (SEQ ID NO: 750), DOM7r-17 (SEQ ID NO: 751), DOM7r-18 (SEQ ID NO: 752), DOM7r-19 (SEQ ID NO: 753). Figures 9A-9B are an illustration of the amino acid sequences of VHs that are linked to rat serum albumin (RSA). The illustrated sequences are from the VHs designated as DOM7r-20 (SEQ ID NO: 754), DOM7r-21 (SEQ ID NO: 755), DOM7r-22 (SEQ ID NO: 756), DOM7r-23 (SEQ ID NO: 757), DOM7r-24 (SEQ ID NO: 758), DOM7r-25 (SEQ ID NO: 759), DOM7r-26 (SEQ ID NO: 760), DOM7r-27 (SEQ ID NO: 761), DOM7r-28 (SEQ ID NO: 762), DOM7r-29 (SEQ ID NO: 763), DOM7r-30 (SEQ ID NO: 764), DOM7r -31 (SEQ ID NO: 765), DOM7r-32 (SEQ ID NO: 766), and DOM7r-33 (SEQ ID NO: 767). Figure 10 illustrates the amino acid sequences of various camelid VHHS that bind to mouse serum albumin, which are disclosed in International Publication Number WO 2004/041862. Sequence A (SEQ ID NO: 768), sequence B (SEQ ID NO: 769), sequence C (SEQ ID NO: 770), sequence D (SEQ ID NO: 771), sequence E (SEQ ID NO: 772), sequence F (SEQ ID NO: 773), sequence G (SEQ ID NO: 774), sequence H (SEQ ID NO: 775), sequence I (SEQ ID NO: 776), sequence J (SEQ ID NO: 777), sequence K (SEQ ID NO: 778), sequence L (SEQ ID NO 779), sequence M (SEQ ID NO 780), sequence N (SEQ ID NO 781), sequence O (SEQ ID NO 782), sequence P (SEQ ID NO 783), sequence Q (SEQ ID NO 784) The Figures 11A-11V illustrate the amino acid sequences of several variable domains of human immunoglobulin having binding specificity for human TNFR1 The presented amino acid sequences are contiguous without gaps, the symbol ~ has been inserted into the sequences to indicate the locations of the regions complementarity determinants (CDRs) CDR1 is flanked by ~, the CDR2 is flanked by ~~, and CDR3 is flanked by Figures 12A-12B illustrating the amino acid sequences of several variable domains of human immunoglobulin having binding specificity for mouse TNFR1. The amino acid sequences presented are contiguous without gaps, the symbol - has been inserted in some of the sequences to indicate the locations of the complementarity determining regions (CDRs) CDR1 is flanked by ~, CDR2 is flanked by ~~, and CDR3 is flanked by ~~~ DESCRIPTION DETAILED OF THE INVENTION Within this specification, the invention has been described with reference to the modalities, in a manner that makes it possible to write a clear and concise descriptive memory. It is intended and it should be appreciated that the modalities can be combined variably or separate without departing from the invention As used herein, the term "ligand" refers to a polypeptide comprising a domain having binding specificity for a desired objective. Preferably, the binding domain is a single variable domain of immunoglobuhne (e.g. VH, VL, VHH), which has binding specificity for a desired target antigen (eg, a receptor protein) The binding domain may also comprise one or more complementing determinant regions (CDRs) of a single immunoglobulin variable domain that has binding specificity for a desired target antigen in a suitable format, such that the binding domain has binding specificity for the target antigen. For example, complementarity determining regions can be grafted onto a suitable scaffold or protein backbone, such as an affluent, a SpA scaffold, an LDL class A receptor domain, or an EGF domain. In addition, the ligand can be monovalent. alloy (eg, a monomer of dAb), bivalent (homo-bivalent, hetero-bivalent), or multivalent (homo-multivalent, hetero-multivalent), as described herein. Therefore, "ligands" include polypeptides that consist of a dAb, include the polypeptides consisting essentially of this dAb, the polypeptides comprising a dAb (or the complementarity determining regions of a dAb) in a suitable format, such as an antibody format (e.g., IgG type format) , scFv, Fab, Fab ', F (ab') 2), or a scaffolding or skeleton of suitable protein, such as an affibody, an SpA scaffold, an LDL class A receptor domain, or an EGF domain, double specific ligands comprising a dAb that binds to a first target protein, antigen, or epitope (eg, example, I L-1 R 1 or TNFR-1), and a second dAb that binds to another target protein, antigen, or epitope (e.g., serum albumin), and the multispecific ligands described herein. link can also be a protein domain comprising a binding site for a desired target, for example a protein domain is selected from an affluent, an SpA domain, an LDL class A receptor domain, a domain of EGF, and an avimer (see, for example, U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301) The phrase "a single immunoglobulin variable domain" refers to a variable region of ant iibody (VH, VHH, VL) that binds specifically to an antigen or epitope, independently of other regions or V domains, however, as the term is used herein, a single immunoglobulin variable domain may be present in a (for example, homo- or hetero-multimer) with other variable regions or variable domains, where the other regions or domains are not required for antigen binding by the single immunoglobulin variable domain (i.e., where the single domain variable immunoglobulin binds to the antigen independently of the additional variable domains) "A single immunoglobulin variable domain" encompasses not only a single variable domain polypeptide of isolated antibody, but also larger polypeptides comprising one or more monomers of a single variable domain polypeptide sequence of antibody. A "domain antibody" or "dAb" is the same as a "single immunoglobulin variable domain" polypeptide, as the term is used herein. A single immunoglobulin variable domain polypeptide, as used herein, refers to a single variable domain mammalian immunoglobulin polypeptide, preferably human, but also includes a rodent (eg, as is know in International Publication Number WO 00/29004, the content of which is incorporated herein by reference in its entirety), or the camelid VHH dAbs Camelid dAbs are single-variable variable immunoglobulin domain peptides that are derived from species including camel, llama, alpaca, dromedary, and guanaco, and comprise naturally occurring chain-heavy antibodies. VHH molecules VHH molecules are approximately 10 times smaller than IgG molecules, and as individual polypeptides, they are very stable, resisting extreme conditions of pH and temperature. As used herein, the term "dose" refers to the amount of agent (e.g., dAb ant? -IL-1R1, TNFR1 antagonist) administered to a subject all at once (unit dose), or in two or more administrations for a defined time interval. For example, the dose may refer to the amount of agent (eg, dAb ant? -IL-1 R1, TNFR1 antagonist) administered to a subject during the course of 1 day (24 hours) (daily dose), two days , one week, two weeks, three weeks, or one or more months (for example, by a single administration, or by two or more administrations) The interval between doses can be any desired amount of time Two immunoglobulin domains are "complementary" "when they belong to families of structures that form pairs or cognate groups, or that are derived from such families and retain this characteristic. For example, a VH domain and a VL domain of an antibody are complementary, two VH domains are not complementary, and two VL domains are not complementary Complementary domains can be found in other members of the immunoglobulin super family, such as the Va and Vp (oyyd) domains of the T-cell receptor. Domains that are artificial, such as domains based on protein scaffolds that do not bind epitopes unless they are designed to do so, are not complementary In the same way, two domains based (for example) on a Immunoglobulin domain and a fibronectin domain, are not complementary "Immunoglobulin" refers to a family of polypeptides that retain the characteristic immunoglobulin fold of the antibody molecules, which contains two β-sheets, and usually, a conserved disulfide bond The members of the immunoglobulm super family are involved in many aspects of the cellular and non-cellular interactions m vivo, including the widely spread roles in the immune system (e.g., antibodies, T-cell receptor molecules, and the like), involvement in cell adhesion (e.g., ICAM molecules), and intracellular signaling (e.g., receptor molecules, such as the factor receptor. platelet derived growth) The present invention is applicable to all molecules of the immunoglobulin super family that possess binding domains. Preferably, the present invention relates to antibodies. A "domain" is a structure of folded protein that retains its tertiary structure independently of the rest of the protein In general terms, the domains are responsible for e the separate functional properties of the proteins, and in many cases they can be added, removed, or transferred to other proteins without loss of function of the rest of the protein and / or the domain. A "single antibody variable domain" is a domain of folded polypeptide comprising characteristic sequences of the antibody variable domains Accordingly, it includes the entire variable antibody domains and the modified variable domains, for example, wherein one or more cycles have been replaced by sequences that are not characteristic of the variable domains of antibody, or variable domains of antibody that have been truncated or that comprise N- or C-terminal extensions, as well as the folded fragments of the variable domains that retain at least in part the binding activity and specificity of the length domain complete The term "repertoire" refers to a collection of various variants, for example polypeptide variants, which differ in their primary structure. A library used in the present invention will encompass a repertoire of polypeptides comprising at least 1,000 members. The term "library" "refers to a mixture of heterogeneous polypeptides or nucleic acids. The library is composed of members, each of which has a single polypeptide or nucleic acid sequences. To this extent, "library" is synonymous with "repertoire." Differences in sequence between members of the library are responsible for the diversity present in the library The library can take the form of a simple mixture of polypeptides or nucleic acids, or may be in the form of organisms or cells, for example bacteria, viruses, animal or plant cells, and the like, transformed with a nucleic acid library. Preferably, each organism or single cell contains only one or a number limited of members of the library Conveniently, nucleic acids are incorporated into expression vectors, in order to allow expression of the polypeptides encoded by nucleic acids In a preferred aspect, therefore, a library can take the form of a population of host organisms, each organism containing one or more copies of an expression vector containing a single member of the library in the form of nucleic acid, which can be expressed to produce its corresponding polypeptide member. Therefore, the population of host organisms has the potential to encode a large repertoire of genetically diverse polypeptide variants. An "antibody" (eg, IgG, IgM, IgA, IgD or IgE) or fragment (such as a Fab, F (ab ') 2, disulfide-linked Fv, scFv, closed conformation multispecific antibody, disulfide-linked scFv, diabody), either derived from any species that naturally produces an antibody, or created by recombinant DNA technology, either isolated from serum, B-cells, hibpdomas, transfectomas, yeast, or bacteria) A "double specific ligand" is a ligand that comprises a first single variable domain of immunoglobulin and a second single variable domain of immunoglobulin, such as is defined herein, wherein the variable regions are capable of binding to two different antigens or two epitopes on the same antigen, which are not normally bound by an immuno monospecific globulin For example, the two epitopes may be on the same hapten, but they are not the same epitope, or they may be sufficiently adjacent to be linked by a monospecific ligand. The specific double ligands according to the invention are composed of variable domains having different specificities, and do not contain pairs of mutually complementary variable domains having the same specificity. The specific double ligands and the methods suitable for the preparation of double specific ligands are given to be known from the International Publications Numbers WO 2004/058821, WO 2004/003019, and WO 03/002609, and the total teachings of each of these published international applications are incorporated herein by reference. An "antigen" is a molecule that it is linked by a ligand according to the present invention. Typically, the antigens are ligated by antibody ligands, and are capable of eliciting an antibody response in vivo. It can be a polypeptide, protein, nucleic acid, or other molecule. Generally speaking, the specific double ligands according to the invention are selected for their specificity against a particular antigen in the case of conventional antibodies and fragments thereof. , the antibody binding site by the variable cycles (L1, L2, L3, and H1, H2, H3) is able to bind to the antigen An "epitope" is a structure unit conventionally linked by a VH / V pair of immunoglobulin Epitopes define the minimum binding site for an antibody, and therefore, represent the specificity target of an antibody In the case of a single-domain antibody, an epitope represents the unit structure bound by a variable domain in isolation A "universal structure" is a single sequence of antibody structure corresponding to the regions of an antibody conserved in the sequence, as defined by Kabat ("Sequence of Proteins Immunological Interest", as defined by the United States Department of Health and Human Services), or corresponding to repertoire or immunoglobulm structure of the human germline, as defined by Chothia and Lesk, (1987) J Mol Biol 196910-917 The invention provides the use of a single structure, or of a set of these structures, that has been found that allow the derivation of virtually any link specificity through variation in hyper-vapable regions alone "Half-life" is time that is needed to reduce the serum concentration of the ligand by 50 percent, in vitro, for example, due to degradation of the ligand and / or to the elimination or sequestration of the ligand by natural mechanisms The ligands of the invention are stabilized in vivo, and their life is increased by their binding to molecules that resist degradation and / or elimination or sequestration Typically, these molecules are proteins that occur naturally, that they themselves have a long half-life m alive The average life of a Ligand is increased if its functional activity persists, m live, for a longer period than a similar ligand that is not specific for the molecule that increases the half-life. Accordingly, a specific ligand for HSA and a target molecule are compared to the same ligand, where the specificity for HSA is not present, ie, it does not bind to HSA, but binds to another molecule. For example, it can be linked to a second epitope on the same molecule Typically, the half-life increases by 10 percent, 20 percent, 30 percent, 40 percent, 50 percent, or more. increases in the range of 2x, 3x, 4x, 5x, 10x, 20x, 30x, 40x, 50x or more of the half-life. Alternatively, or in addition, increases in the range of up to 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, 150x of the half-life are possible. As referred to herein, the term "competes" means that the binding of a first epitope with its cognate epitope binding domain is inhibited when a second epitope is linked to its cognate epitope binding domain. For example, the link can be inhibited, for example, by physically blocking a link domain, or by altering the structure or environment of a link domain, so that its affinity or avidity is reduced. by an epitope Alignments of amino acid and nucleotide sequences, and homology, similarity, or identity, as defined herein, are preferably prepared and determined Using the algorithm of the BLAST 2 Sequences, using the default parameters (Tatusova, TA et al., FEMS Microbio! Lett, 114 187-188 (1999)). In an alternative way, the BLAST algorithm (version 20) is used for the sequence alignment, with the parameters set in the default values BLAST (Basic Local Ahgnment Search Tool) is the heuristic search algorithm used by the blastp, blastn, blastx, tblastn, and tblastx programs , these programs ascribe meaning to their findings using the statistical methods of Karlin and Altschul, 1990, Proc Nati Acad Sci USA 87 (6) 2264-8 The invention relates to dAb monomers that bind to IL-1R1, and which inhibit the binding of IL-1 (for example, IL-1 a and / or I L-1 ß) with the receptor, but not inhibiting the binding of IL-1ra with IL-1R1, and with ligands comprising these monomers of dAb These dAb monitors and monomers are useful iles as therapeutic agents for the treatment of inflammation, diseases, or other conditions mediated wholly or in part by the biological functions induced by the binding of IL-1 with IL-1R1 (eg, local or systemic inflammation, elaboration of mediators inflammatories (e.g., I L-6, IL-8, TNF), fever, activation of immune cells (e.g., lymphocytes, neutrophils), anorexia, hypotension, leucopema thrombocytopenia) The dAb ligands or monomers of the invention can be bind with IL-1R1, and inhibit the function of IL-1R1, without interfering with the inhibitory pathways of endogenous IL-1R1, such as the binding of endogenous IL-1ra with endogenous IL-1R1 In accordance with the foregoing, this ligand or dAb monomer can be administered to a subject to complement the endogenous regulatory pathways that inhibit the activity of IL-1R1 or IL-1m vivo In addition, the dAb ligands or monomers that bind to IL-1R1 and do not inhibit the binding of IL-1ra to IL-1R1, provide advantages to be used as agents of diagnosis, because they can be used to bind and detect, quantify or measure IL-1R1 in a sample, and will not compete with IL-1ra in the sample for the link with IL-1R1. Accordingly, it can be make an accurate determination of whether there is IL-1R1 and how much in the sample The dAb monomers that bind to IL-1R1 and that inhibit IL-1 binding (eg, IL-1a and / or I L-1 ß) with the receptor, but do not inhibit the binding of I L-1 ra with IL-1R1, are also useful as research tools For example, 'this dAb monomer can be used to identify agents (eg, other dAbs, small organic molecules) that bind to IL-1R1, but do not inhibit the binding of I L-1 ra to IL-1R1 In an illustrative example, an agent or a collection of agents to be tested for their ability to inhibit the binding of IL-1 to IL-1R1, in a competitive IL-1R1 receptor binding assay, such as the receptor binding assay described in the present. Then we can study the agents that inhibit the binding of IL-1 with IL-1R1 in this assay, in a similar competitive IL-1R1 receptor binding assay, to see if they compete with a dAb monomer that binds to IL-1R1 but does not inhibit the binding of I L-1 ra with IL-1R1. The competitive binding in this assay indicates that the agent binds to IL-1R1 and that it inhibits the binding of IL-1 to the receptor, but does not inhibit the binding of I L-1 ra to the receptor. Ligands and Monomers of dAb that bind with IL-1R1. The invention provides ligands comprising a dAb (eg, a specific double ligand comprising this dAb, dAb monomer) that binds to IL-1R1 with a Kd of 300 nM to 5 pM (ie, 3 x 10"). at 5 x 10"12 M), preferably 50 nM to 20 pM, more preferably 5 nM to 200 pM, and most preferably from 1 nM to 100 pM, for example 1x 10'7 M or less, preferably 1 x 10"8 M or less, more preferably 1 x 10" 9 M or less, conveniently 1 x 10'10 M or less, and most preferably 1 x 10"11 M or less, and / or an index constant Kdesact? empty of 5 x 10'1 s "1 to 1 x 10" 7 s'1, preferably of 1 x 1 O "2 s'1 to 1 x 10" 6 s' \ more preferably of 5 x 10"3 s" 1 to 1x 10"5 s'1, for example 5 x 10" 1 s "1 or less, preferably 1 x 10" 2 s "1 or less, in a convenient manner 1 x 10"3 s" 1 or less, more preferably 1 x 1 O "4 s'1 or less, still more preferably 1 x 10" 5 s "1 or less, and most preferably 1 x 10"6 s" 1 om enos, determined by surface plasmon resonance. Preferably, the dAb ligand or monomer inhibits the binding of IL-1 (e.g., I L-1 a and / or I L-1 ß) with the IL-1R1, pro example in a receptor binding assay, with an inhibitory concentration 50 (IC50) that is equal to or less than about 1 μM, for example an IC50 of from about 500 nM to about 50 pM, preferably from about 100 nM to about 50 pM , more preferably from about 10 nM to about 100 pM, and conveniently from about 1 nM to about 100 pM; for example, of about 50 nM or less, preferably about 5 nM or less, more preferably about 500 pM or less, conveniently about 200 pM or less, and most preferably about 100 pM or less. less. Preferably, the ligand or dAb binds to human IL-1R1, and inhibits binding of human IL-1 (e.g., I L-1 a and / or I L-1 ß) to human IL-1R1 , and inhibits signaling through human IL-R1 in response to the IL-1 binding. Preferably, the dAb ligand or monomer neutralizes (inhibits the activity of) IL-1 or IL-1R1 in a conventional assay (e.g., the IL-1-induced release of interleukin-8 by the MRC-5 cells, the IL-1-induced release of interleukin-6 by whole blood cells) with a neutralizing dose 50 (ND50) that is less than or equal to about 1 μM, for example an ND50 of about 500 nM at about 50 pM, preferably from about 100 nM to about 50 pM, more preferably from about 10 nM to about 100 pM, conveniently from about 1 nM to about 100 pM; for example, of about 50 nM or less, preferably about 5 nM or less, more preferably about 500 pM or less, conveniently about 200 pM or less, and most preferably about 100 pM or less. less. For example, the dAb ligand or monomer can inhibit the IL-1-induced release (e.g., induced by I L-1 a or I-1 ß) of interleukin-8 by MRC-5 cells (ATCC, Number Access CCL-171) in an in vitro assay with an ND50 which is < 10 μM, < 1 μM, < 100 nM, < 10 nM, < 1 nM, < 500 pM, < 300 pM, < 100 pM, or < 10 pM. In another example, the dAb ligand or monomer can inhibit the IL-1-induced release (eg, induced by IL-1a or by IL-1β) of interleukin-6 in a whole-blood test in vitro with a ND50 which is <; 10 μM, < 1 μM, < 100 nM, < 10 nM, < 1 nM, < 500 pM, < 300 pM, < 100 pM, or < 10 pM. The ligand may be monovalent (e.g., a dAb monomer) or multivalent (e.g., specific double, multi-specific) as described herein. In particular embodiments, the ligand is a dAb monomer that binds to human IL-1R1, and comprises a moiety that extends the half-life (as described herein), such as a polyethylene glycol moiety. In other modalities, the ligand is multivalent, and it comprises two or more dAb monomers that bind to IL-1R1. Multivalent ligands may contain two or more copies of a particular dAb that binds to IL-1R1, or may contain two or more dAbs that bind to IL-1R1. For example, as described herein, the ligand may be a dimer, trimer, or multimer comprising two or more copies of a particular dAb that binds to IL-1R1, or may comprise two or more different dAbs that are link to IL-1R1. In some examples, the ligand is a homo-dimer or homo-trimer comprising two or three copies of a particular dAb that binds to IL-1R1, respectively. Preferably, a multivalent ligand does not substantially agonize I L-1 R 1 (acts as an IL-1 R 1 agonist) in a conventional cellular assay (i.e., when present at a concentration of 1 nM, nM, 100 nM, 1 μM, 10 μM, 100 μM, 1,000 μM, or 5,000 μM, results in no more than about 5 percent of the activity mediated by IL-1R1 and induced by IL-1 (100 picograms / milliliter) in the test). In certain embodiments, the multivalent ligand contains two or more dAbs that bind to a desired epitope or domain of IL-1R1. For example, the multivalent ligand may comprise two or more copies of a dAb that compete with I L-1 ra for the linkage with IL-1R1. In another example, the multivalent ligand may comprise two or more copies of a dAb that does not compete with I L-1 ra for the linkage with IL-1R1. In other modalities, the multivalent ligand contains two 0 more dAbs that are linked to different epitopes or domains of 1 L-1 R 1 In one example, the multivalent ligand comprises a first dAb that binds to a first epitope of IL-1R1, and a second dAb that binds to a second epitope different from IL-1R1 The higandos of this type they can be linked to IL-1R1 with high activity, and can be more selective for binding to cells that overexpress I L-1 R 1 or that express I L-1 R 1 on their surface at a high density, than others Ligand formats, such as dAb monomers In certain embodiments, the dAb monomers or domains of the invention are effective in a model disease (e.g., an inflammatory disease), when an effective amount is administered. Generally speaking, a The effective amount in an inflammatory disease model is from about 1 milligram / kilogram to about 10 milligrams / kilogram (eg, about 1 milligram / kilogram, about 2 milligrams / kilogram, about 3 milligrams / kilogram, about approximately 3 milligrams / kilogram, approximately 4 milligrams / kilogram, approximately 5 milligrams / kilogram, approximately 6 milligrams / kilogram, approximately 7 milligrams / kilogram, approximately 8 milligrams / kilogram, approximately 9 milligrams / kilogram, or approximately 10 milligrams / kilogram) models of chronic inflammatory disease described herein are recognized by experts in this field as predictors of the Therapeutic efficacy in humans The prior art does not suggest the use of dAb ligands or monomers, as described herein, in these models, or that they are effective. Several suitable animal models of respiratory disease are known in the art, and are recognized. by experts in the field as predictors of therapeutic efficacy in humans For example, suitable animal models of respiratory disease include models of chronic obstructive pulmonary disease (see Groneberg, DA et al., Respiratory Research 5.18 (2004)), and asthma models (see Coffman et al., J Exp Med 201 (12) 1875-1879 (2001)) For example, the ligand or monomer of dAb may be effective in the mouse model of chronic obstructive pulmonary disease induced by the Tobacco smoke (COPD) (see, for example, Wright JL and Churg A, Chest 22301 S-306S (2002)) For example, administration of an effective amount of the dAb ligand or monomer can reduce or delay the establishment of the symptoms of chronic obstructive pulmonary disease, compared with adequate control In particular modalities , the dAb ligand or monomer is effective in a conventional arthritis model (e.g., inflammatory arthritis, osteoartptis) Several suitable models are known in the art, e.g., the mouse collagen-induced arthritis model (cf. for example, Juarranz et al., Arthritis Research and Therapy, 1 R1034-R1045 (2005)), arthritis induced by rat adjuvant (see, for example, Halloran, M. et al., J. Immunol., 65: 7492 (1999), Halloran, M. et al., Arthritis Rheum., 39: 810 (1996)), osteoarthritis experimental rabbit (see, for example, Spriet, et al., Osteoarthritis and Cartilage, 13: 171-179 (2005)), and several mouse osteoarthritis models (see, for example, Helminen et al., Rheumatology, 41: 848 -856 (2002)). For example, arthritis can be induced in DBA / 1 mice by injecting the animals with an adjuvant emulsion Arthrogen-CIA and collagen Arthrogen-CIA (MD-Biosciences). Approximately 21 days after injection, the ligand or dAb monomer to be tested can be administered (for example, by intraperitoneal injection). Clinical arthritic grades can be measured on a scale of 0 to 4 for each of the four limbs of the animals, assigning zero for a normal limb, and assigning 4 for a maximally inflamed limb with involvement of multiple joints. Administration of an effective amount of dAb ligand or monomer may reduce the average arthritic rating of the sum of the four extremities in this model of mouse collagen-induced arthritis, eg, the average arthritic rating of the sum of the four extremities it can be reduced by about 1 to about 16, by about 3 to about 16, by about 6 to about 16, by about 9 to about 16, or by about 12 to about 16, compared to an appropriate control, or may delay the establishment of arthritis symptoms, for example, for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days , about 6 days, about 7 days, about 10 days, about 14 days, about 21 days, or about 28 days, compared with an adequate control In another example, administration of an effective amount of the ligand can result in an arthritic rating average of the sum of the four extremities in the mouse collagen induced arthritis model from 0 to about 3, from about 3 to about 5, from about 5 to about 7, from about 7 to about 15, from about 9 to about 15, from about 10 to about 15, from about 12 to about e 15, or from about 14 to about 15 In other embodiments, the dAb ligand or monomer is effective in the mouse arthritis model "ARE (Kontoyiannis et al., J Exp Med 196 1563-74 (2002)) For example , administration of an effective amount of the ligand can reduce the average arthritic rating in the mouse arthritis model? ARE, for example, by about 0 1 to about 25, by about 05 to about 2 5, by about 1 to about 25, about 1-5 to about 25, or about 2 to about 2.5, compared to a suitable control. In another example, administration of an effective amount of the ligand may delay the establishment of arthritis symptoms in the model. of mouse arthritis, for example, for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 14 days, about 21 days , or about 28 days, compared to a suitable control In another example, administration of an effective amount of the ligand can result in an average arthritic rating in the arthritis model of the mouse ARE from 0 to about 05, from about 05 to about 1, from about 1 to about 1 5, from about 1.5 to about 2, or from about 2 to about 2.5. In other embodiments, the dAb ligand or monomer is effective in the mouse inflammatory bowel disease (IBD) model (Kontoyiannis et al., J. Exp. Med. 196: 1563-74 (2002)). For example, administration of an effective amount of the ligand may reduce the grade of acute and / or chronic inflammation average in the mouse inflammatory bowel disease model, eg, by approximately 0.1 to about 25, about 05 to about 25, about 1 to about 25, about 1 5 to about 25, or about 2 to about 25, compared to a suitable control. In another example, the administration of an effective amount of the ligand may delay the establishment of the symptoms of inflammatory bowel disease in the mouse inflammatory bowel disease model, eg, for approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, about 6 days, about 7 days, about 10 days, about 14 days, about 21 days, or about 28 days, compared with an adequate control In another example, administration of an effective amount of the ligand can result in an inflammation rating acute and / or average chronic in the disease model in of the intestine? mouse ARE from 0 to about 05, from about 05 to about 1, from about 1 to about 1 5, from about 1 5 to about 2, or from about 2 to about 25 In other embodiments, the ligand or the dAb monomer is effective in the model of inflammatory bowel disease induced by mouse dextran-sodium sulfate (DSS) (see Okayasu I et al., Gastroenterology 98694-702 (1990), Podoisky K, J Gasteroenterol Supplement 38 XV 63-66 (2003)) for example, administration of an effective amount of the ligand may reduce the average severity score in the inflammatory bowel disease model induced by mouse dextran-sodium sulfate, for example, about 01 to about 25, about 05 to about 25, about 1 to about 25, about 1.5 to about 25, or about 2 to about 25, compared to a suitable control. In another example, the administration of an amount Effectiveness of the ligand may delay the establishment of the symptoms of inflammatory bowel disease in the inflammatory bowel disease model induced by mouse dextran-sodium sulfate, for example, for approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 10 days, approximately 14 days, approximately 21 days, or approximately 28 days, compared to an adequate control In another example, the administration of an effective amount of the ligand can result in an average severity rating in the model of inflammatory bowel disease induced by mouse dextran-sodium sulfate from 0 to about 05, from about 0.5 to about 1, from about 1 to about 1 5, from about 1 5 to about 2, or from approximately 2 to approximately 2.5. In some embodiments, the ligand comprises a dAb that specifically binds to IL-1R1, which inhibits the binding of IL-1 (e.g., I L-1 a and / or I L-1 ß) to the receptor, but which does not inhibit the binding of IL-1ra with IL-1R1, and competes for binding with IL-1R1 with the dAb selected from the group consisting of DOM4-122-23 (SEQ ID NO: 1), DOM4-122 -24 (SEQ ID NO: 2), DOM4-122 (SEQ ID NO: 95), DOM4-122-1 (SEQ ID NO: 96), DOM4-122-2 (SEQ ID NO: 97), DOM4-122 -3 (SEQ ID NO.98), DOM4-122-4 (SEQ ID NO: 99), DOM4-122-5 (SEQ ID NO: 100), DOM4-122-6 (SEQ ID NO: 101), DOM4 -122-7 (SEQ ID NO: 102), DOM4-122-8 (SEQ ID NO: 103), DOM4-122-9 (SEQ ID NO: 104), DOM4-122-10 (SEQ ID NO: 105) , DOM4-122-11 (SEQ ID NO: 106), DOM4-122-12 (SEQ ID NO: 107), DOM4-122-13 (SEQ ID NO: 108) DOM4-122-14 (SEQ ID NO: 109), DOM4-122-15 (SEQ ID NO: 110) DOM4-122-16 (SEQ ID NO: 111), DOM4-122-17 (SEQ ID NO: 112) DOM4-122-18 (SEQ ID NO: 113), DOM4-122-19 (SEQ ID NO: 114) DOM4-122-20 (SEQ ID NO: 115), DOM4-122-21 (SEQ ID NO: 116) DOM4-122-22 (SEQ ID NO: 117), DOM4-122-25 (SEQ ID NO: 118) DOM4-122-26 (SEQ ID NO: 119), DOM4-122-27 (SEQ ID NO: 120) DOM4-122-28 (SEQ ID NO: 121), DOM4-122-29 (SEQ ID NO: 122) DOM4-122-30 (SEQ ID NO: 123), DOM4-122-31 (SEQ ID NO: 124) DOM4-122-32 (SEQ ID NO: 125), DOM4-122-33 (SEQ ID NO: 126) DOM4-122-34 (SEQ ID NO: 127), DOM4-122-35 (SEQ ID NO: 128) DOM4-122-36 (SEQ ID NO: 129), DOM4-122-37 (SEQ ID NO: 130) DOM4-122-38 (SEQ ID NO: 131), DOM4- 122-39 (SEQ ID NO 132 DOM4-122-40 (SEQ ID NO 133) DOM4- 122-41 (SEQ ID NO 134 DOM4- 122-42 (SEQ ID NO 135) DOM4- 122-43 (SEQ ID NO 136 DOM4- 122-44 (SEQ ID NO 137) DOM4-122-45 (SEQ ID NO 138 DOM4- 122-46 (SEQ ID NO 139) DOM4- 122-47 (SEQ ID NO 140 DOM4- 122-48 ( SEQ ID NO 141) DOM4- 122-49 (SEQ ID NO 142 DOM4- 122-50 (SEQ ID NO 143) DOM4- 122-51 (SEQ ID NO 144 DOM4- 122-52 (SEQ ID NO 145) DOM4- 122 -54 (SEQ ID NO 146 DOM4- 122-55 (SEQ ID NO 147) DOM4- 122-56 (SEQ ID NO 148 DOM4- 122-57 (SEQ ID NO 149) DOM4- 122-58 (SEQ ID NO 150 DOM4 122-59 (SEQ ID NO 151) DOM4-122-60 (SEQ ID NO 152 DOM4-122-61 (SEQ ID NO. 153) DOM4- 122-62 (SEQ ID NO 154 DOM4- 122-63 (SEQ ID NO. 155) DOM4-122-64 (SEQ ID NO: 156 DOM4-122-65 (SEQ ID NO: 157) DOM4-122-66 (SEQ ID NO 158 DOM4- 122-67 (SEQ ID NO 159) DOM4- 122-68 ( SEQ ID NO 160 DOM4- 122-69 (SEQ ID NO 161) DOM4- 122-70 (SEQ ID NO 162 DOM4- 122-71 (SEQ ID NO 163) DOM4-122-72 (SEQ ID NO: 164), and DOM4-122-73 (SEQ ID NO: 165) In some embodiments, the ligand comprises a dAb that specifically binds to the I L-1 R, inhibits IL binding -1 (for example, IL-1a and / or IL-1β) with the receptor, but does not inhibit the binding of L-1 ra with IL-1R1, and comprises an amino acid sequence having a sequence identity of amino acids of at least about 80 percent, at least about 85 percent, at least about 90 percent, at least about 91 percent, at least about 92 percent, at least about 93 percent, at least about 94 percent, at least about 95 percent, at least about 96 percent, at least about 97 percent, at least about 98 percent, or at least about 99 percent with the amino acid sequence of a dAb selected from the group consisting of DOM4-122-23 (SEQ ID NO 1), DOM4-122-24 (SEQ ID NO 2), DOM4-122 ( SEQ ID NO 95), DOM4-122-1 (SEQ ID NO 96), DOM4-122-2 (SEQ ID NO 97), DOM4-122-3 (SEQ ID NO 98), DOM4-122-4 (SEQ ID NO 99), DOM4-122-5 (SEQ ID NO 100), DOM4-122-6 (SEQ ID NO 101), DOM4-122-7 (SEQ ID NO 102), DOM4-122-8 (SEQ ID NO 103) ), DOM4-122-9 (SEQ ID NO 104), DOM4-122-10 (SEQ ID NO 105) DOM4-122-11 (SEQ ID NO. 106 DOM4-122-12 (SEQ ID NO. 107) DOM4-122-13 (SEQ ID NO. 108 DOM4-122-14 (SEQ ID NO. 109) DOM4-122-15 (SEQ ID NO 110 DOM4-122-16 (SEQ ID NO 111) DOM4-122-17 (SEQ ID NO 112 DOM4-122-18 (SEQ ID NO 113) DOM4-122-19 (SEQ ID NO 114 DOM4-122 -20 (SEQ ID NO 115) DOM4-122-21 (SEQ ID NO 116 DOM4-122-22 (SEQ ID NO 117) DOM4-122-25 (SEQ ID NO 118 DOM4-122-26 (SEQ ID NO 119) DOM4-122-27 (SEQ ID NO 120 DOM4-122-28 (SEQ ID NO 121) DOM4-122-29 (SEQ ID NO 122 DOM4-122-30 (SEQ ID NO 123) DOM4-122-31 (SEQ ID NO 124 DOM4-122-32 (SEQ ID NO 125) DOM4-122-33 (SEQ ID NO 126 DOM4-122-34 (SEQ ID NO 127) DOM4-122-35 (SEQ ID NO 128 DOM4-122-36 ( SEQ ID NO 129), DOM4- 122-37 (SEQ ID NO: 130 DOM4- 122-38 (SEQ ID NO 131), DOM4- 122-39 (SEQ ID NO: 132 DOM4- 122-40 (SEQ ID NO 133), DOM4- 122-41 (SEQ ID NO: 134 DOM4- 122-42 (SEQ ID NO 135), DOM4- 122-43 (SEQ ID NO: 136 DOM4- 122-44 (SEQ ID NO 137), DOM4- 122-45 (SEQ ID NO: 138 DOM4- 122-46 (SEQ ID NO 139), DOM4- 122-47 (SEQ ID NO: 140 DOM4- 122-48 (SEQ ID NO 141), DOM4- 122-49 (SEQ ID NO: 142 DOM4- 122-50 SEQ ID NO 143), DOM4- 122-51 (SEQ ID NO: 144 DOM4- 122-52 SEQ ID NO 145), DOM4- 122-54 (SEQ ID NO: 146 DOM4- 122-55 SEQ ID NO 147), DOM4- 122-56 (SEQ ID NO: 148 DOM4- 122-57 SEQ ID NO 149), DOM4- 122-58 (SEQ ID NO: 150 DOM4- 122-59 SEQ ID NO 151), DOM4- 122-60 (SEQ ID NO: 152 DOM4- 122-61 kSEQ ID NO 153), DOM4- 122-62 (SEQ ID NO: 154 DOM4- 122-63 [SEQ ID NO 155), DOM4- 122-64 (SEQ ID NO: 156 DOM4 122-65 [SEQ ID NO 157), DOM4- 122-66 (SEQ ID NO: 158 DOM4 -122-67 [SEQ ID NO 159), DOM4- 122-68 (SEQ ID NO: 160 DOM4 -122-69 [SEQ ID NO 161), DOM4- 122-70 (SEQ ID NO: 162 DOM4 -122-71 [SEQ ID NO 163), DOM4-122-72 (SEQ ID NO: 164), and DOM4-122-73 (SEQ ID NO 165). In some embodiments, the ligand comprises a dAb that binds to IL-1R1, and which competes with any of the dAbs disclosed herein by the linkage to IL-1R1 (e.g., human L-1 R 1) ). In preferred embodiments, the ligand comprises a dAb monomer selected from the group consisting of DOM4-122-23 and DOM4-122-24. For example, the ligand can be a monomer, or it can be a hetero- or homo-dimer, trimer, or oligomer of these dAbs. If desired, the ligand may further comprise a fraction that extends the half-life, such as a polyethylene glycol fraction. In some embodiments, the ligand comprises a dAb monomer selected from the group consisting of DOM4-122-23 and DOM4-122-24, and a dAb monomer that binds to serum albumin. For example, the ligand can be a double specific ligand comprising DOM4-122-23 and DOM7h-8, or DOM4-122-23 and DOM7h-8. The dAb monomer may comprise any suitable immunoglobulin variable domain, and preferably comprises a human variable domain, or a variable domain comprising human framework regions. In certain embodiments, the dAb monomer comprises a universal structure, as described herein. The universal structure may be a V (V? Or VK) structure, such as a structure comprising the amino acid sequences of structure encoded by the human germline immunoglobulin gene segment DPK1, DPK2, DPK3, DPK4, DPK5, DPK6, DPK7, DPK8, DPK9, DPK10, DPK12, DPK13, DPK15, DPK16, DPK18, DPK19, DPK20, DPK21, DPK22, DPK23, DPK24, DPK25, DPK26, or DPK28. If desired, the VL structure may further comprise the amino acid sequence of structure encoded by the genetic segment of immunoglobulin of the human germline J? 1, J? 2, J? 3, J? 4, or J? 5 In other embodiments, the universal structure may be a VH structure, such as a structure comprising the amino acid sequence of structure encoded by the genetic segment of human germline immunoglobulin DP4, DP7, DP8, DP9, DP10, DP31, DP33, DP38, DP45, DP46, DP47, DP49, DP50, DP51, DP53, DP54, DP65, DP66, DP67, DP68, or DP69. If desired, the VH structure may further comprise the amino acid sequence of structure encoded by the human germline immunoglobulin gene segment JH1, JH2, JH3, JH4, JH4b, JH5, and JH6. In certain embodiments, the monomer of dAb comprises one or more structure regions comprising an amino acid sequence that is the same as the amino acid sequence of a corresponding structure region encoded by a genetic segment of the human germline antibody, or the amino acid sequences of one or more of the structure regions collectively comprise up to five amino acid differences in relation to the amino acid sequence of this region of corresponding structure encoded by a genetic segment of human germline antibody In other embodiments, the amino acid sequences of FW1, FW2, FW3, and FW4 of the dAb monomer are equal to the amino acid sequences of the regions s of corresponding structures encoded by a genetic segment of human germline antibody, or the amino acid sequences of FW1, FW2, FW3, and FW4 collectively contain up to 10 amino acid differences relative to the amino acid sequences of the corresponding structure regions encoded by this genetic segment of the antibody from the human germline In other modalities, the monomer of dAb comprises the regions FW1, FW2, and FW3, and the amino acid sequence of these regions FW1, FW2, and FW3 are the same as the amino acid sequences of the corresponding structure regions encoded by the genetic segments of human antibodies. the human germline In particular embodiments, the ligand of the dAb monomer comprises the structure of VL DPK9, or a VH structure selected from the group consisting of DP47, DP45, and DP38. The dAb monomer may comprise a linkage for a generic ligand, such as protein A, protein L, and protein G In certain embodiments, the ligand or dAb monomer is substantially resistant to accumulation. For example, in some embodiments, less than about 10 percent accumulates. , less than about 9 percent, less than about 8 percent, less than about 7 percent, less than about 6 percent, less than about 5 percent, less than about 4 percent, less than about 3 percent, less than about 2 percent, or less than about 1 percent of the dAb ligand or monomer when a solution of 1 to 5 milligrams / milliliter, 5 to 10 milligrams / milliliter, of 10 to 20 milligrams / milliliter, of 20 to 50 milligrams / milliliter, 50 to 100 milligrams / milliliter, 100 to 200 milligrams / milliliter, or 200 to 500 milligrams / milliliter of ligand or dAb in a solvent, which is routinely used for drug formulation, such as serum, regulated serum, citrate-regulated serum, water, an emulsion, and any of these solvents with a suitable excipient, such as those approved by the FDA, is maintained at approximately 22 ° C, 22-25 ° C, 25-30 ° C, 30-37 ° C, 37-40 ° C, 40-50 ° C, 50-60 ° C, 60-70 ° C, 70-80 ° C, 15-20 ° C, 10-15 ° C , 5-10 ° C, 2-5 ° C, 0-2 ° C, -10 ° to 0 ° C, -20 ° C to -10 ° C, -40 ° C to -20 ° C, from -60 ° C to -40 ° C, or from -80 ° C to -60 ° C, for a period of time, for example, of about 10 minutes, 1 hour, 8 hours , 24 hours, 2 days, 3 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 1 year, or 2 years The accumulation can be evaluated using any suitable method, such as, through the microscope, the assessment of the turbidity of a solution by visual inspection or spectroscopy or any other suitable method. Preferably, the accumulation is evaluated by dynamic light scattering. The dAb ligands or monomers that are resistant to the accumulation provide several advantages. For example, these dAb ligands or monomers can be easily produced in a high yield as soluble proteins by expression using a suitable biological production system, such as E. coli, and can be formulated and / or stored at higher concentrations than conventional polypeptides, and with less accumulation and loss of activity. In addition, dAb ligands or monomers that are resistant to accumulation can be produced more economically than other antigen or epitope binding polypeptides (eg, conventional antibodies). For example, in general terms, the preparation of antigen or epitope binding polypeptides intended for in vivo applications, includes processes (eg, gel filtration), which remove accumulated polypeptides. Failure to remove these aggregates can result in a preparation that is not suitable for in vivo applications, due, for example, to the fact that aggregates of an antigen binding polypeptide that is intended to act as an antagonist, can function as an agonist by induction of cross-linking or pooling of the target antigen. Protein aggregates can also reduce the efficacy of therapeutic polypeptides by inducing an immune response in the subject to which they are administered. In contrast, the accumulative-resistant dAb ligands or monomers of the invention can be prepared for in vivo applications without the need to include process steps that remove the aggregates, and can be used in in vivo applications. without the aforementioned drawbacks caused by the polypeptide aggregates In some embodiments, the dAb ligand or monomer is deployed in a reversible manner when heated to a temperature (Ts) and cooled to a temperature (Te), where Ts is greater than the melting temperature (Tm) of dAb, and Te is less than the melting temperature of dAb. For example, the dAb monomer can be deployed in a reversible manner when heated to 80 ° C and cooled to about room temperature. A pohpeptide that is deployed in a reversible manner loses the function that is displayed, but gains again the function after refolding These polypeptides are distinguished from polypeptides that accumulate when they unfold or that fold back in a proper manner (poorly folded pohpeptides), ie, do not regain their function The deployment and retraction of pohpeptides can be evaluated, for example, by direct or indirect detection of the structure of the polypeptide using any suitable method. For example, the structure of the pohpeptide can be detected by circular dichroism (CD) (for example, UV-distant CD, near-UV CD), fluorescence (for example, fluorescence of the side chains of tptophophane), susceptibility to proteolysis, nuclear magnetic resonance (NMR), or by detecting or measuring a function of the polypeptide that depends on the appropriate fold (eg, binding to the target ligand, binding to the generic ligand). In one example, deployment of the polypeptide is evaluated using a functional assay wherein the loss of the binding function (e.g., the binding of a generic and / or target ligand, the binding of a substrate) indicates that the polypeptide is displayed. Deployment and folding extension of a dAb ligand or monomer can be determined using a deployment or denaturing curve. A deployment curve can be produced by plotting the temperature as the ordinate, and the relative concentration of the folded polypeptide as the abscissa. The relative concentration of the folded dAb ligand or monomer can be determined directly or indirectly using any suitable method (eg, circular dichroism, fluorescence, binding assay). For example, a solution of ligand or dAb monomer can be prepared, and the ellipticity of the solution is determined by circular dichroism. The obtained ellipticity value represents a relative concentration of the folded dAb ligand or monomer of 100 percent. The dAb ligand or monomer in the solution is then displayed by increasing the temperature of the solution, and the ellipticity is determined in appropriate increments (for example, after each increment of a degree in temperature). The dAb ligand or monomer in solution is then refolded by increasingly reducing the temperature of the solution, and the ellipticity is determined in appropriate increments The data can be graphed to produce a deployment curve and a replication curve The deployment and withdrawal curves have a characteristic sigmoidal shape that includes a portion where the dAb ligand or monomer molecules fold, a deployment / retraction transition where the molecules of ligand or monomer of dAb unfold to different degrees, and a portion where the dAb ligand or monomer molecules unfold The intercept of the y-axis of the fold curve is the relative amount of the refolded dAb ligand or monomer recovered. recovery of at least about 50 percent, or at least about 60 percent, or at least about 70 percent, or at least about 75 percent, or at least about 80 percent, or at least about 85 percent, or at least about 90 percent, or at least about 95 percent , indicates that the ligand or monomer of dAb is deployed in a reversible manner. In a preferred embodiment, the reversibility of the deployment of the dAb ligand or monomer is determined by the preparation of a dAb ligand or monomer solution, and plotting the curves of deployment and withdrawal by heat. The dAb ligand or monomer solution can be prepared in any suitable solvent, such as an aqueous buffer having a suitable pH to allow the ligand or the solvent to dissolve. dAb monomer (e.g., a pH that is about 3 units above or below the isoelectric point (pl)). The ligand or monomer solution of dAb is concentrated enough to allow it to unfold / fold. For example, the ligand or dAb monomer solution can be from about 0.1 μM to about 100 μM, or preferably from about 1 μM to about 10 μM. If the melting temperature (Tm) of the ligand or dAb monomer is known, the solution can be heated to about 10 degrees below the Tm (Tm-10), and the fold can be evaluated by ellipticity or fluorescence ( example, UV-distant CD scan from 200 nanometers up to 250 nanometers, CD of fixed wavelength at 235 nanometers or 225 nanometers, fluorescent emission spectra of tryptophan from 300 to 450 nanometers with excitation at 298 nanometers), to provide 100 percent relative dAb ligand or monomer folded. Then the solution is heated to at least 10 degrees above the Tm (Tm + 10) in previously determined increments (for example, increments of about 0.1 to about 1 degree), and ellipticity or fluorescence is determined at each increment. Then, the dAb ligand or monomer is refolded by cooling it at least to Tm-10 in previously determined increments, and ellipticity or fluorescence is determined at each increment. If the melting temperature of the ligand or the monomer of dAb, the solution can be deployed by heating increasingly from about 25 ° C to about 100 ° C, and then folding back down to increasingly cool to at least about 25 ° C, and determining the ellipticity or fluorescence at each increase in heating and cooling. The obtained data can be graphed to produce a deployment curve and a fallback curve, where the intercept of the y-axis of the fallback curve is the relative amount of the recovered refolding protein. In some embodiments, the dAb monomer does not comprise a variable domain of camelid immunoglobulin, or one or more amino acids of structure that are unique to the variable immunoglobulin domains encoded by the germline antibody segments of the camelid germ line Preferably, the dAb ligand or monomer is secreted in an amount of at least about 0 5 milligrams / liter, when expressed in E coli or in Pichia species (e.g., P pastons) In other preferred embodiments, the dAb monomer is secreted in an amount of at least about 075 milligrams / liter, at least about 1 milligram / liter, at least about 4 milligrams / liter, at least about 5 milligrams / liter, at least about 10 milligrams / liter, when less about 15 milligrams / liter, at least about 20 milligrams / liter, at least about 25 milligrams / liter, at least about 30 r milligrams / liter, at least about 35 r milligrams / liter, at least about 40 r milligrams / liter, at least about 45 thousand grams / liter, or at least about 50 thousand grams / liter, or at least about 100 ml igramos / tro, or at least approximately 200 mi igramos / liter, or at least approximately 300 mi igramos / htro, or at least approximately 400 mi igramos / liter, or at least approximately 500 mi igramos / liter, or at least approximately 600 mi igramos / htro, or at least approximately 700 mi igramos / liter, or at least approximately 800 mi igramos / liter, or at least approximately 900 mi igramos / tro, or at least approximately 1 gram / liter, when expressed in E. coli or in Pichia species (eg, P pastons) In other preferred embodiments, the dAb monomer is secreted in an amount of at least about 1 milligram / liter to at least about 1 gram / liter, from at least about 1 milligram / liter to at least about 750 milligrams / liter, from at least about 100 milligrams / liter to at least about 1 gram / liter, from at least about 200 milligrams / liter to when less about 1 gram / liter, from at least about 300 milligrams / liter to when less about 1 gram / liter, from at least about 400 milligrams / liter to at least about 1 gram / liter, from at least about 500 milligrams / liter to at least about 1 gram / liter, from at least about 600 milligrams / liter to at least about 1 gram / liter, from at least about 700 milligrams / liter to at least about 1 gram / liter, from at least about 800 milligrams / liter to at least about 1 gram / liter, or at least about 900 milligrams / liter to at least about 1 gram / liter, when expressed in E. coli or in Pichia species (eg, P. pastoris). Although dAb ligands and monomers described herein can be secreted when expressed in E. coli or in Pichia species (eg, P. pastoris), they can be produced using any suitable method, such as synthetic chemical methods or biological production methods that do not use E. coli or Pichia species. DAb monomers that bind with the serum albumin. The ligand of the invention may comprise a dAb monomer that is linked to serum albumin (SA) with a Kd of 1 nM to 500 μM (i.e., x 10"9 to 5x10" 4), preferably 100 nM to 10 μM. Preferably, for a specific double ligand comprising a first anti-serum albumin dAb, and a second dAb with another target, the affinity (for example, Kd and / or Kdesact? Vad0, measured by surface plasmon resonance, for example using BiaCore) of the second dAb for its purpose, is from 1 to 100,000 times (preferably from 100 to 100,000, more preferably from 1,000 to 100,000, or from 10,000 to 100,000 times) the affinity of the first dAb for serum albumin. For example, the first dAb binds to serum albumin with an affinity of approximately 10 μM, while the second dAb binds to its target with an affinity of 100 pM. Preferably, serum albumin is human serum albumin (HSA). In one embodiment, the first dAb (or a dAb monomer) is linked to serum albumin (e.g., human serum albumin) with a Kd of about 50, preferably 70, and more preferably 100, 150, or 200 nM. In certain embodiments, the dAb monomer that binds to the serum albumin resists accumulation, reversibly unfolds, and / or comprises a region of structure as described above for the dAb monomers that bind to IL-1R1. In particular embodiments, the antigen binding fragment of an antibody that binds to serum albumin is a dAb that binds to human serum albumin. In certain embodiments, dAb binds to human serum albumin, and competes for binding to albumin with a dAb selected from the group consisting of DOM7m-16 (SEQ ID NO: 723), DOM7m-12 (SEQ ID NO: 724), DOM7m-26 (SEQ ID NO: 725), DOM7r- 1 (SEQ ID NO: 726), DOM7r-3 (SEQ ID NO: 727), DOM7r-4 (SEQ ID NO: 728), DOM7r-5 (SEQ ID NO: 729), DOM7r-7 (SEQ ID NO: 730), DOM7r-8 (SEQ ID NO: 731), DOM7h-2 (SEQ ID NO: 732), DOM7h-3 (SEQ ID NO: 733), DOM7h-4 (SEQ ID NO: 734), DOM7h-6 (SEQ ID NO: 735), DOM7h-1 (SEQ ID NO: 736), DOM7h-7 (SEQ ID NO: 737), DOM7h-8 (SEQ ID NO: 746), DOM7r-13 (SEQ ID NO: 747), DOM7r-14 (SEQ ID NO: 748), DOM7h-22 (SEQ ID NO: 739), DOM7h-23 (SEQ ID NO: 740), DOM7h-24 (SEQ ID NO: 741), DOM7h-25 (SEQ ID NO: 742), DOM7h-26 (SEQ ID NO: 743), DOM7h-21 (SEQ ID NO: 744), DOM7h -27 (SEQ ID NO: 745), DOM7r-15 (SEQ ID NO: 749), DOM7r-16 (SEQ.
ID NO: 750), DOM7r-17 (SEQ ID NO: 751), DOM7r-18 (SEQ ID NO: 752), DOM7r-19 (SEQ ID NO: 753), DOM7r-20 (SEQ ID NO: 754), DOM7r-21 (SEQ ID NO: 755), DOM7r-22 (SEQ ID NO: 756), DOM7r-23 (SEQ ID NO: 757), DOM7r-24 (SEQ ID NO: 758), DOM7r-25 (SEQ ID NO: 759), DOM7r-26 (SEQ ID NO: 760), DOM7r-27 (SEQ ID NO: 761), DOM7r-28 (SEQ ID NO: 762), DOM7r-29 (SEQ ID NO: 763), DOM7r-30 (SEQ ID NO: 764), DOM7r-31 (SEQ ID NO: 765), DOM7r-32 (SEQ ID NO: 766), and DOM7r-33 (SEQ ID NO: 767). In certain embodiments, dAb binds to human serum albumin, and comprises an amino acid sequence having an amino acid sequence identity of at least about 80 percent, or at least about 85 percent, or at least about 90 percent, or at least about 95 percent, or at least about 96 percent, or at least about 97 percent, or at least about 98 percent, or at least about 99 percent, with the amino acid sequence of a dAb selected from the group that consists of DOM7m-16 (SEQ ID NO: 723), DOM7m-12 (SEQ ID NO: 724), DOM7m-26 (SEQ ID NO: 725), DOM7r-1 (SEQ ID NO: 726), DOM7r-3 ( SEQ ID NO: 727), DOM7r-4 (SEQ ID NO: 728), DOM7r-5 (SEQ ID NO: 729), DOM7r-7 (SEQ ID NO: 730), DOM7r-8 (SEQ ID NO: 731) , DOM7h-2 (SEQ ID NO: 732), DOM7h-3 (SEQ ID NO: 733), DOM7h-4 (SEQ ID NO: 734), DOM7h-6 (SEQ ID NO: 735), DOM7h-1 (SEQ ID NO: 736), DOM7h-7 (SEQ ID NO: 737), DOM7h-8 (SEQ ID NO: 746), DOM7r-13 (SEQ ID NO: 747), DOM7r-14 (SEQ ID NO: 748), DOM7h-22 (SEQ ID NO: 739), DOM7h-23 (SEQ ID NO: 740), DOM7h-24 (SEQ ID NO: 741), DOM7h -25 (SEQ ID NO: 742), DOM7h-26 (SEQ ID NO: 743), DOM7h-21 (SEQ ID NO: 744), DOM7h-27 (SEQ ID NO: 745), DOM7r-15 (SEQ ID NO. : 749), DOM7r-16 (SEQ ID NO: 750), DOM7r-17 (SEQ ID NO: 751), DOM7r-18 (SEQ ID NO: 752), DOM7r-19 (SEQ ID NO: 753), DOM7r- 20 (SEQ ID NO: 754), DOM7r-21 (SEQ ID NO: 755), DOM7r-22 (SEQ ID NO: 756), DOM7r-23 (SEQ ID NO: 757), DOM7r-24 (SEQ ID NO: 758), DOM7r-25 (SEQ ID NO: 759), DOM7r-26 (SEQ ID NO: 760), DOM7r-27 (SEQ ID NO: 761), DOM7r-28 (SEQ ID NO: 762), DOM7r-29 (SEQ ID NO: 763), DOM7r-30 (SEQ ID NO: 764), DOM7r-31 (SEQ ID NO: 765), DOM7r-32 (SEQ ID NO: 766), and DOM7r-33 (SEQ ID NO: 767). For example, the dAb that binds to serum albumin human can comprise an amino acid sequence having an amino acid sequence identity of at least about 90 percent, or at least about 95 percent, or at least about 96 percent, or at least about 97 percent, or at least approximately 98 percent, or at least approximately 99 percent with DOM7h-2 (SEQ ID NO 732), DOM7h-3 (SEQ ID NO 733), DOM7h-4 (SEQ ID NO 734), DOM7h-6 (SEQ ID NO 735), DOM7h-1 (SEQ ID NO 736), DOM7h-7 (SEQ ID NO 737), DOM7h-8 (SEQ ID No. 746), DOM7r-13 (SEQ ID No. 747), DOM7r-14 (SEQ ID No. 748), DOM7h-22 (SEQ ID No. 739), DOM7h-23 (SEQ ID NO 740), DOM7h-24 (SEQ ID No. 741), DOM7h-25 (SEQ ID No. 742), DOM7h-26 (SEQ ID No. 743), DOM7h-21 (SEQ ID No. 744), and DOM7h-27 (SEQ ID NO 745) The identity of amino acid sequences is preferably determined using a suitable sequence alignment algorithm and the default parameters, such as BLAST P (Karlin and Altschul, Proc Nati Acad Sci USA 87 (6) 2264-2268 ( 1990)) In the most particular modalities, the dAb is a dAb of V? which binds to human serum albumin, and has an amino acid sequence selected from the group consisting of DOM7h-2 (SEQ ID NO 732), DOM7h-3 (SEQ ID NO 733), DOM7h-4 (SEQ ID NO 734), DOM7h-6 (SEQ ID No. 735), DOM7h-1 (SEQ ID No. 736), DOM7h-7 (SEQ ID No. 737), DOM7h-8 (SEQ ID NO: 746), DOM7r-13 (SEQ ID NO: 747), and DOM7r-14 (SEQ ID NO: 748), or a VH dAb having an amino acid sequence selected from the group consisting of DOM7h-22 (SEQ ID NO: 739), DOM7h-23 (SEQ ID NO: 740), DOM7h-24 (SEQ ID NO: 741), DOM7h-25 (SEQ ID NO: 742), DOM7h-26 (SEQ ID NO: 743) ), DOM7h- 21 (SEQ ID NO: 744), and DOM7h-27 (SEQ ID NO: 745). In other embodiments, the antigen binding fragment of an antibody that binds to serum albumin is a dAb that binds to human serum albumin, and comprises the complementarity determining regions of any of the above amino acid sequences. Suitable camelid VHH that binds to serum albumin includes those disclosed in International Publication Number WO 2004/041862 (Ablynx N.V.), and herein (SEQ ID NOs: 768-784). In certain embodiments, camelid VHH binds to human serum albumin, and comprises an amino acid sequence having an amino acid sequence identity of at least about 80 percent, or at least about 85 percent, or at least about 90 percent, or at least about 95 percent, or at least about 96 percent, or at least about 97 percent, or at least about 98 percent, or at least about 99 percent with SEQ ID NO: 768, SEQ ID NO: 769, SEQ ID NO: 770, SEQ ID NO: 771, SEQ ID NO: 772, SEQ ID NO: 773, SEQ ID NO: 774, SEQ ID NO: 775, SEQ ID NO: 776, SEQ ID NO: 777, SEQ ID NO: 778, SEQ ID NO: 779, SEQ ID NO: 780, SEQ ID NO: 781, SEQ ID NO: 782, SEQ ID NO: 783, or SEQ ID NO: 784. The identity of amino acid sequences is preferably determined using a suitable sequence alignment algorithm and the default parameters, such as BLAST P (Karlin and Altschul, Proc. Nati. Acad. Sci. USA 87 (6): 2264-2268 (1990)). In some embodiments, the ligand comprises an anti-serum albumin dAb that competes with any anti-serum albumin dAb as disclosed herein for binding to serum albumin (e.g., human serum albumin). DAb monomers that bind to the Tumor Necrosis Factor-1 Receptor (TNFR1). The ligand of the invention may comprise a dAb monomer that is linked to TNFR1. TNFR1 is a transmembrane receptor that contains an extracellular region that binds to the ligand, and an intracellular domain that lacks intrinsic signal transduction activity, but that can be associated with signal transduction molecules. The complex of TNFR1 with the bound TNF contains three chains of TNFR1 and three chains of TNF. (Banner et al., Cell 73 (3) 431-445 (1993)). The TNF ligand is present as a trimer, which binds to three chains of TNFR1. (Id.). The three chains of TNFR1 are tightly clustered together in the receptor-ligand complex, and This grouping is a prerequisite for signal transduction mediated by TNFR1. In fact, multivalent agents that bind to TNFR1, such as anti- -TNFR1 antibodies, can induce clustering of TNFR1 and signal transduction in the absence of TNF, and are commonly used as TNFR1 agonists (See, for example, Belka et al., EMBO, 74 (6) .1156-1165 (1995), Mandik-Nayak et al., J Immunol, 167-1920-1928 ( 2001)) In accordance with the above, multivalent agents that bind TNFR1 in general are not effective TNFR1 antagonists, even when they block TNFa binding to TNFR1. The extracellular region of TNFR1 comprises an amino-terminal segment of 13 amino acids. (amino acids 1-13 of SEQ ID NO 996 (human), amino acids 1-13 of SEQ ID NO 997 (mouse)), Domain 1 (amino acids 14-53 of SEQ ID NO 996 (human), amino acids 14-53 of SEQ ID NO 997 (mouse)), Domain 2 (amino acids 54-97 of SEQ ID NO.996 (human), amino acids 54-97 of SEQ ID NO 997 ( mouse)), Domain 3 (amino acids 98-138 of SEQ ID NO: 996 (human), amino acids 98-138 of SEQ ID NO: 997 (mouse)), and Domain 4 (amino acids 139-167 of SEQ ID NO 996 (human), amino acids 139-167 of SEQ ID NO 997 (mouse)), which is followed by a proximal membrane region (amino acids 168-182 of SEQ ID NO 996 (human) , amino acids 168-183 SEQ ID NO 997 (mouse)). (See Banner et al., Cell 73 (3) 431-445 (1993), and Loetscher et al., Cell 61 (2) 351-359 (1990)) Domains 2 and 3 make contact with the ligand linked (TNFβ, TNFα) (Banner et al., Cell, 73 (3) 431-445 (1993)) The extracellular region of TNFR1 also contains a region referred to as the ligand pre-binding domain or PLAD domain (amino acids 1-53 of SEQ ID NO 996 (human), amino acids 1-53 of SEQ ID NO 997 ( Mouse)) (The Government of the United States of America, International Publication Number WO 01/58953, Deng et al., Nature Medicine, doi 10 1038 / nm1304 (2005)) TNFR1 is covered from the surface of cells in vivo to through a process that includes the proteolysis of TNFR1 in Domain 4, or in the proximal membrane region (amino acids 168-182 of SEQ ID NO 213, amino acids 168-183 of SEQ ID NO 215, respectively), to produce a soluble form of TNFR1 Soluble TNFR1 retains the ability to bind to TNFa, and thus works well mo an endogenous inhibitor of TNFa activity The extracellular region of human TNFR1 has the following amino acid sequence LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPGPGQ DTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTV CGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHA GFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSGTT (SEQ ID NO 996) The extracellular region of TNFR1 mupno. { Mus musculus) has the following amino acid sequence: LVPSLGDREKRDSLCPQGKYVHSKNNSICCTKCHKGTYLVSDCPSPGR DTVCRECEKGTFTASQNYLRQCLSCKTCRKEMSQVEISPCQADKDTVC GCKENQFQRYLSETHFQCVDCSPCFNGTVTIPCKETQNTVCNCHAGFF LRESECVPCSHCKKNEECMKLCLPPPLANVTNPQDSGTA (SEQ ID NO: 997). The anti-TNFR1 dAbs suitable for use in the invention (eg, the ligands described herein), have binding specificity for the Tumor Necrosis Factor-1 Receptor (TNFR1; p55; CD120a). Preferably, the TNFR1 antagonists do not have binding specificity for Tumor Necrosis Factor-2 (TNFR2), or do not substantially antagonize TNFR2. A TNFR1 antagonist does not substantially antagonize TNFR2 when the antagonist (1 nM, 10 nM, 100 nM, 1 μM, 10 μM, or 100 μM) results in an inhibition no greater than about 5 percent of the activity mediated by TNFR2 induced by TNFa (100 picograms / milliliter) in a conventional cellular assay. In certain embodiments, the dAb monomer that binds to TNFR1 resists accumulation, unfolds in a reversible manner, and / or comprises a region of structure as described above for the dAb monomers that bind to IL-1R1. . Anti-TNFR1 dAbs and suitable ligands comprising these dAbs do not induce cross-linking or clustering of TNFR1 on the surface of the cells, which can lead to receptor activation and signal transduction In particular embodiments, the ligand comprises a dAb ant? -TNFR1 that binds to Domain 1 of TNFR1 In the most particular embodiments, the ligand comprises an ant? -TNFR1 dAb that binds with Domain 1 of TNFR1, and which competes with TAR2m-21-23 for binding to mouse TNFR1, or competes with TAR2h-205 for binding to human TNFR1 In certain embodiments, the anti-TNFR1 dAb it is linked to Domain 2 and / or Domain 3 of TNFR1 In particular modalities, the dAb ant? -TNFR1 competes with TAR2h-10-27, TAR2h-131-8, TAR2h-15-8, TAR2h-35-4, TAR2h-154-7, TAR2h-154-10, or TAR2h-185-25 for the binding with TNFR1 (for example, human and / or mouse TNFR1) Preferably, the antibacterial dTb monomers -TNFR1 suitable for use in the ligands of the invention bind to TNFR1 with a Kd of 300 nM to 5 pM (ie, 3 x 107 to 5 x 1012 M), preferably 50 nM to 20 pM, more preferably 5 nM to 20 0 pM, and most preferably from 1 nM to 100 pM, for example 1 x 107 M or less, preferably 1 x 108 M or less, more preferably 1 x 109 or less, in a convenient manner 1 x 1010 M or less, and most preferably 1 x 1011M or less, and / or a Kdesact? Vad0 index constant of 5 x 101 s 1 to 1 x 107 s 1, preferably 1 x 102 s 1 to 1 x 106 s \ more preferably 5 x 103 to 1 x 105 s 1, for example 5 x 101 s 1 or less, preferably 1 x 102 s 1 or less, in a manner convenient 1 x 10 s or less, and most preferably 1 x 104 s 1 or less, still more preferably 1 x 105 s 1 or less, and most preferably 1 x 106 s 1 or less, determined by resonance of superficial plasmon. (The Kd = Kdesact? Vado / Kact? Vado) Certain anti? -TNFR1 dAb monomers suitable for use in the invention bind specifically to human TNFR1 with a Kd of 50 nM to 20 pM, and a constant of Kdesact index? vad0 of 5 x 101 s 1 to 1 x 107 s 1, determined by surface plasmon resonance Some monomers of dAb ant? -TNFR1 inhibit the binding of TNFa to TNFR1 For example, some monomers of dAb anti-TNFR1 inhibit the binding of TNFa to TNFR1 with an inhibitory concentration 50 (IC50) from 500 nM to 50 pM, preferably from 100 nM to 50 pM, more preferably from 10 nM to 100 pM, conveniently from 1 nM to 100 pM, for example 50 nM or less, preferably 5 nM or less, more preferably 500 pM or less, more preferably in a convenient manner of 200 pM or less, and most preferably 100 pM or less. Preferably, TNFR1 is the Human TNFR1 Other monomers of dAb ant? -TNFR1 do not inhibit the binding of TNFa to TNFR1, but inhibit signal transduction mediated through TNFR1 For example, an anti-TNFR1 dAb monomer can inhibit the TNFa-induced clustering of TNFR1, which precedes signal transduction through TNFR1. For example, certain monomers of dAb anti- ? -TNFR1 can be linked with TNFR1 and inhibit signaling mediated by TNFR1, but do not substantially inhibit the binding of TNFa to TNFR1. For example, the monomer of dAb ant? -TNFR1 inhibits the cross-linking or clustering of TNFR1 induced by TNFa on the surface of a cell These dAbs (e.g., TAR2m-21-23 described herein) are convenient, because they can antagonize cell surface TNFR1, but do not substantially reduce the inhibitory activity of endogenous soluble TNFR1. For example, dAb ant? - TNFR1 can bind to TNFR1, but inhibits the binding of TNFa to TNFR1 in a receptor binding assay by no more than about 10 percent, no more than about 5 percent, no more than about 4 percent , no more than about 3 percent, no more than about 2 percent, or no more than about 1 percent. Also, in these embodiments, the anti-TNF1 dAb inhibits the TNFα-induced cross-linking of TNFα and / or the TNFR1-mediated signaling in a conventional cellular assay by at least about 10 percent., by at least about 20 percent, by at least about 30 percent, by at least about 40 percent, by at least about 50 percent, by at least about 60 percent, by at least about 70 percent, by at least approximately 80 percent, by at least approximately 90 percent, by at least approximately 95 percent, by at least approximately 99 percent. Accordingly, administration of a ligand comprising this dAb monomer to a mammal in need thereof can complement the endogenous regulatory pathways that inhibit TNFa activity and TNFR1 m activity alive. Preferably, the dAb ligand or monomer neutralizes (inhibits the activity of) TNFR1 in a conventional assay (e.g., the conventional L929 or HeLa IL-8 assays described herein), with a neutralizing dose of 50 ( ND50) from 500 nM to 50 pM, preferably from 100 nM to 50 pM, more preferably from 10 nM to 100 pM, conveniently from 1 nM to 100 pM; for example 50 nM or less, preferably 5 nM or less, more preferably 500 pM or less, conveniently 200 pM or less, and most preferably 100 pM or less In other embodiments, the anti-TNFR1 dAb monomer binds to TNFR1, and antagonizes the activity of TNFR1 in a conventional cellular assay (eg, the conventional L929 or HeLa IL-8 assays described herein) with an ND50 of < 100 nM, and at a concentration of < 10 μM, the dAb agonizes the activity of TNFR1 by < .5 percent in the trial. In other embodiments, the anti-TNFR1 dAb monomer binds specifically to TNFR1 with a Kd described herein, and inhibits lethality in a septic shock model induced by standard mouse LPS / D-galactosamine (ie, prevents lethality or reduces lethality by at least approximately 10 percent, compared to adequate control). Preferably, the anti-TNFR1 dAb monomer inhibits lethality by at least about 25 percent, or by at least about 50 percent, compared to a suitable control, in a septic shock model induced by LPS / Standard mouse D-galactosamine, when administered at about 5 milligrams / kilogram or more, preferably at about 1 milligram / kilogram. In particular embodiments, the anti-TNFR1 dAb monomer or a ligand of the invention comprising this dAb monomer, does not agonize substantially to TNFR1 (acts as a TNFR1 agonist) in a conventional cellular assay, such as conventional nnssaayyos L929 or HeLa IL-8 described in this (ie, when present at a concentration of 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM, 1000 μM, or 5,000 μM, results in no more than about 5 percent of the activity mediated by TNFR1 induced by TNFa (100 picograms / milliliter) in the assay). In other embodiments, the ligand comprises a domain antibody monomer (dAb) that specifically binds to the tumor necrosis factor-1 receptor (TNFR1, p55, CD120a) with a Kd of 300 nM to 5 pM, and comprises a amino acid sequence that is at least about 80 by percent, at least about 85 percent, at least about 90 percent, at least about 91 percent, at least about 92 percent, at least about 93 percent, at least about 94 percent, at least about 95 percent, at least about 96 percent, at least about 97 percent, at least about 98 percent, or at least about 99 percent homologous to the amino acid sequence or a dAb selected from the group consisting of TAR2h-12 (SEQ ID NO: 785), TAR2h-13 (SEQ ID NO: 786), TAR2h-14 (SEQ ID NO: 787), TAR2h-16 (SEQ ID NO: 788) ), TAR2h-17 (SEQ ID NO: 789), TAR2h-18 (SEQ ID NO: 790), TAR2h-19 (SEQ ID NO: 791), TAR2h-20 (SEQ ID NO: 792), TAR2h-21 ( SEQ ID NO: 793), TAR2h-22 (SEQ ID NO: 794), TAR2h-23 (SEQ ID NO: 795), TAR2h-24 (SEQ ID NO: 796), TAR2h-25 (SEQ ID NO: 797), TAR2h-26 (SEQ ID NO: 798), TAR2h-27 (SEQ ID NO: 799), TAR2h-29 (SEQ ID NO: 800) ), TAR2h-30 (SEQ ID NO: 801), TAR2h-32 (SEQ ID NO: 802), TAR2h-33 (SEQ ID NO: 803), TAR2h-10-1 (SEQ ID NO: 804), TAR2h- 10-2 (SEQ ID NO: 805), TAR2h-10-3 (SEQ ID NO: 806), TAR2h-10-4 (SEQ ID NO: 807), TAR2h-10-5 (SEQ ID NO: 808), TAR2h-10-6 (SEQ ID NO: 809), TAR2h-10-7 (SEQ ID NO: 810), TAR2h-10-8 ( SEQ ID NO: 811), TAR2h-10-9 (SEQ ID NO: 812), TAR2h-10-10 (SEQ ID NO: 813), TAR2h-10-11 (SEQ ID NO: 814), TAR2h-10- 12 (SEQ ID NO: 815), TAR2h-10-13 (SEQ ID NO: 816), TAR2h-10-14 (SEQ ID NO: 817), TAR2h-10-15 (SEQ ID NO: 818), TAR2h-10-16 (SEQ ID NO: 819), TAR2h-10-17 (SEQ ID NO: 820), TAR2h-10-18 (SEQ ID NO: 821), TAR2h-10-19 (SEQ ID NO: 822), TAR2h-10-20 (SEQ ID NO: 823), TAR2h-10-21 (SEQ ID NO: 824), TAR2h-10-22 (SEQ ID NO: 825), TAR2h-10-27 (SEQ ID NO: 826), TAR2h-10-29 (SEQ ID NO: 827), TAR2h-10-31 (SEQ ID NO: 828), TAR2h-10-35 (SEQ ID NO: 829), TAR2h-10-36 (SEQ ID NO: 830), TAR2h-10-37 (SEQ ID NO: 831), TAR2h-10-38 (SEQ ID NO: 832) TAR2h-10-45 (SEQ ID NO: 833), TAR2h-10-47 (SEQ ID NO: 834) TAR2h-10-48 (SEQ ID NO: 835), TAR2h-10-57 (SEQ ID NO: 836) TAR2h-10-56 (SEQ ID NO: 837), TAR2h-10-58 (SEQ ID NO: 838) TAR2h-10-66 (SEQ ID NO: 839), TAR2h-10-64 (SEQ ID NO: 840) TAR2h-10-65 (SEQ ID NO: 841), TAR2h-10-68 (SEQ ID NO: 842) TAR2h-10-69 (SEQ ID NO: 843), TAR2h-10-67 (SEQ ID NO: 844) TAR2h-10-61 (SEQ ID NO: 845), TAR2h-10-62 (SEQ ID NO: 846) TAR2h-10-63 (SEQ ID NO: 847), TAR2h-10-60 (SEQ ID NO: 848) TAR2h-10-55 (SEQ ID NO: 849), TAR2h-10-59 (SEQ ID NO: 850) TAR2h-10-70 (SEQ ID NO: 851), TAR2h-34 (SEQ ID NO: 852), TAR2h-35 (SEQ ID NO: 853), TAR2h-36 (SEQ ID NO: 854), TAR2h-37 (SEQ ID NO: 855), TAR2h-38 (SEQ ID NO: 856), TAR2h-39 (SEQ ID NO: 857), TAR2h-40 (SEQ ID NO: 858), TAR2h-41 (SEQ ID NO: 859), TAR2h-42 (SEQ ID NO: 860), TAR2h-43 (SEQ ID NO: 861), TAR2h-44 (SEQ ID NO: 862), TAR2h-45 (SEQ ID NO: 863), TAR2h-47 (SEQ ID NO: 864), TAR2h-48 (SEQ ID NO: 865), TAR2h-50 (SEQ ID NO: 866), TAR2h-51 (SEQ ID NO: 867), TAR2h-66 (SEQ ID NO: 868), TAR2h-67 (SEQ ID NO: 869), TAR2h -68 (SEQ ID NO: 870), TAR2h-70 (SEQ ID NO: 871), TAR2h-71 (SEQ ID NO: 872), TAR2h-72 (SEQ ID NO: 873), TAR2h-73 (SEQ ID NO: 874) ), TAR2h-74 (SEQ ID NO: 875), TAR2h-75 (SEQ ID NO: 876), TAR2h-76 (SEQ ID NO: 877), TAR2h-77 (SEQ ID NO: 878), TAR2h-78 ( SEQ ID NO: 879), TAR2h-79 (SEQ ID NO: 880), TAR2h-15 (SEQ ID NO: 881), TAR2h-131-8 (SEQ ID NO: 882), TAR2h-131-24 (SEQ ID NO: 883), TAR2h-15-8 (SEQ ID NO: 884), TAR2h-15-8-1 (SEQ ID NO : 885), TAR2h-15-8-2 (SEQ ID NO: 886), TAR2h-185-23 (SEQ ID NO: 887), TAR2h-154-10-5 (SEQ ID NO: 888), TAR2h-14 -2 (SEQ ID NO: 889), TAR2h-151-8 (SEQ ID NO: 890), TAR2h-152-7 (SEQ ID NO: 891), TAR2h-35-4 (SEQ ID NO: 892), TAR2h-154-7 (SEQ ID NO: 893), TAR2h-80 (SEQ ID NO: 894), TAR2h-81 (SEQ ID NO: 895), TAR2h- 82 (SEQ ID NO: 896), TAR2h-83 (SEQ ID NO: 897), TAR2h-84 (SEQ ID NO: 898), TAR2h-85 (SEQ ID NO: 899), TAR2h-86 (SEQ ID NO: 900), TAR2h-87 (SEQ ID NO: 901), TAR2h-88 (SEQ ID NO: 902), TAR2h-89 (SEQ ID NO: 903), TAR2h-90 (SEQ ID NO: 904), TAR2h-91 (SEQ ID NO: 905), TAR2h-92 (SEQ ID NO: 906), TAR2h-93 (SEQ ID NO: 907), TAR2h-94 (SEQ ID NO: 908), TAR2h-95 (SEQ ID NO: 909) ), TAR2h-96 (SEQ ID NO: 910), TAR2h-97 (SEQ ID NO: 911), TAR2h-99 (SEQ ID NO: 912), TAR2h-100 (SEQ ID NO: 913), TAR2h-101 ( SEQ ID NO: 914), TAR2h-102 (SEQ ID NO: 915), TAR2h-103 (SEQ ID NO: 916), TAR2h-104 (SEQ ID NO: 917), TAR2h-105 (SEQ ID NO: 918) , TAR2h-106 (SEQ ID NO: 919), TAR2h-107 (SEQ ID NO: 920), TAR2h-108 (SEQ ID NO: 921), TAR2h-109 (SEQ ID NO: 922), TAR2h-110 (SEQ ID NO: 923), TAR2h-111 (SEQ ID NO: 924), TAR2h-112 (SEQ ID NO: 925), TAR2h-113 (SEQ ID NO: 926), TAR2h-114 (SEQ ID NO: 927), TAR2h-115 (SEQ ID NO: 928), TAR2h-116 (SEQ ID NO: 929), TAR2h-117 (SEQ ID NO: 930), TAR2h-118 (SEQ ID NO: 931), TAR2h-119 (SEQ ID NO: 932), TAR2h-120 (SEQ ID NO: 933), TAR2h-121 (SEQ ID NO: 934), TAR2h-122 (SEQ ID NO: 935), TAR2h-123 (SEQ ID NO: 936), TAR2h-124 (SEQ ID NO: 937), TAR2h-125 (SEQ ID NO: 938), TAR2h-126 (SEQ ID NO: 939), TAR2h-127 (SEQ ID NO: 940), TAR2h-128 (SEQ ID NO: 941), TAR2h-129 (SEQ ID NO: 942), TAR2h-130 (SEQ ID NO: 943), TAR2h-131 (SEQ ID NO: 944), TAR2h-132 (SEQ ID NO: 945), TAR2h-133 (SEQ ID NO: 946), TAR2h-151 (SEQ ID NO: 947), TAR2h-152 (SEQ ID NO: 948), TAR2h-153 (SEQ ID NO: 949), TAR2h-154 (SEQ ID NO: 950), TAR2h-159 (SEQ ID NO: 951), TAR2h-165 (SEQ ID NO: 952), TAR2h-166 (SEQ ID NO: 953), TAR2h-168 (SEQ ID NO: 954), TAR2h-171 (SEQ ID NO: 955), TAR2h-172 (SEQ ID NO: 956), TAR2h-173 (SEQ ID NO: 957), TAR2h-174 (SEQ ID NO: 958), TAR2h-176 (SEQ ID NO: 959), TAR2h-178 (SEQ ID NO: 960), TAR2h-201 (SEQ ID NO: 961), TAR2h-202 (SEQ ID NO: 962), TAR2h-203 (SEQ ID NO: 963), TAR2h-204 (SEQ ID NO: 964), TAR2h-185-25 (SEQ ID NO: 965), TAR2h-154-10 (SEQ ID NO: 966), TAR2h-205 (SEQ ID NO: 967), TAR2h-10 (SEQ ID NO: 968), TAR2h-5 (SEQ ID NO: 969), TAR2h-5d1 (SEQ ID NO: 970), TAR2h -5d2 (SEQ ID NO: 971), TAR2h-5d3 (SEQ ID NO: 972), TAR2h-5d4 (SEQ ID NO: 973), TAR2h-5d5 (SEQ ID NO: 974), TAR2h-5d6 (SEQ ID NO: 975), TAR2h-5d7 (SEQ ID NO: 976), TAR2h-5d8 (SEQ ID NO: 977), TAR2h-5d9 (SEQ ID NO: 978), TAR2h-5d10 (SEQ ID NO: 979), TAR2h -5d11 (SEQ ID NO: 980), TAR2h-5d12 (SEQ ID NO: 981), and TAR2h-5d13 (SEQ ID NO: 982). In other embodiments, the ligand comprises a domain antibody monomer (dAb) that specifically binds to the Tumor Necrosis Factor-1 Receptor (TNFR1), with a Kd of 300 nM to 5 pM, and competes for binding to human TNFR1 with a dAb selected from the group consisting of TAR2h-12 (SEQ ID NO: 785), TAR2h-13 (SEQ ID NO: 786), TAR2h-14 (SEQ ID NO: 787), TAR2h-16 (SEQ ID NO: 788), TAR2h-17 (SEQ ID NO: 789), TAR2h-18 (SEQ ID NO: 790), TAR2h-19 (SEQ ID NO: 791), TAR2h-20 (SEQ ID NO: 792), TAR2h-21 (SEQ ID NO: 793), TAR2h-22 (SEQ ID NO: 794), TAR2h-23 (SEQ ID NO: 795), TAR2h-24 (SEQ ID NO: 796), TAR2h-25 (SEQ ID NO: 797), TAR2h-26 (SEQ ID NO: 798), TAR2h-27 (SEQ ID NO: 799), TAR2h-29 (SEQ ID NO: 800), TAR2h-30 (SEQ ID NO: 801), TAR2h-32 (SEQ ID NO: 802), TAR2h-33 (SEQ ID NO: 803), TAR2h-10-1 (SEQ ID NO: 804), TAR2h-10-2 (SEQ ID NO: 805), TAR2h-10-3 (SEQ ID NO: 806), TAR2h-10-4 ( SEQ ID NO: 807), TAR2h-10-5 (SEQ ID NO: 808), TAR2h-10-6 (SEQ ID NO: 809), TAR2h-10-7 (SEQ ID NO: 810), TAR2h-10-8 (SEQ ID NO: 811), TAR2h-10-9 (SEQ ID NO: 812), TAR2h-10-10 ( SEQ ID NO: 813), TAR2h-10-11 (SEQ ID NO: 814), TAR2h-10-12 (SEQ ID NO: 815), TAR2h-10-13 (SEQ ID NO: 816), TAR2h-10- 14 (SEQ ID NO: 817), TAR2h-10-15 (SEQ ID NO: 818), TAR2h-10-16 (SEQ ID NO: 819) TAR2h- • 10-17 (SEQ ID NO: 820 TAR2h- 10-18 (SEQ ID NO: 821) TAR2h- • 10-19 (SEQ ID NO: 822 TAR2h- • 10-20 (SEQ ID NO : 823) TAR2h- • 10-21 (SEQ ID NO: 824 TAR2h- • 10-22 (SEQ ID NO: 825) TAR2h- • 10-27 (SEQ ID NO: 826 TAR2h- • 10-29 (SEQ ID NO : 827) TAR2h- • 10-31 (SEQ ID NO: 828 TAR2h- • 10-35 (SEQ ID NO: 829) TAR2h- • 10-36 (SEQ ID NO: 830 TAR2h- • 10-37 (SEQ ID NO : 831) TAR2h- • 10-38 (SEQ ID NO: 832 TAR2h- • 10-45 (SEQ ID NO: 833) TAR2h- • 10-47 (SEQ ID NO: 834 TAR2h- • 10-48 (SEQ ID NO : 835) TAR2h- -10-57 (SEQ ID NO: 836 TAR2h- • 10-56 (SEQ ID NO: 837) TAR2h- -10-58 (SEQ ID NO: 838 TAR2h- • 10-66 (SEQ ID NO : 839) TAR2h- -10-64 (SEQ ID NO: 840 TAR2h- -10-65 (SEQ ID NO: 841) TAR2h-10-68 (SEQ ID NO: 842) TAR2h- -10-69 (SEQ ID NO : 843) TAR2h-10-67 (SEQ ID NO: 844), TAR2h-10-61 (SEQ ID NO: 845) TAR2h-10-62 (SEQ ID NO: 846), TAR2h-10-63 (SEQ ID NO : 847) TAR2h-10-60 (SEQ ID NO: 848), TAR2h-10-55 (SEQ ID NO: 849) TAR2h-10-59 (SEQ ID NO: 850), TAR2h-10-70 (SEQ ID NO : 851) TAR2h-34 (SEQ ID NO: 85 2), TAR2h-35 (SEQ ID NO: 853), TAR2h-36 (SEQ ID NO: 854), TAR2h-37 (SEQ ID NO: 855), TAR2h-38 (SEQ ID NO: 856), TAR2h-39 (SEQ ID NO: 857), TAR2h-40 (SEQ ID NO: 858), TAR2h-41 (SEQ ID NO: 859), TAR2h-42 (SEQ ID NO: 860), TAR2h-43 (SEQ ID NO: 861) ), TAR2h-44 (SEQ ID NO: 862), TAR2h-45 (SEQ ID NO: 863), TAR2h-47 (SEQ ID NO: 864), TAR2h-48 (SEQ ID NO: 865), TAR2h-50 ( SEQ ID NO: 866), TAR2h-51 (SEQ ID NO: 867), TAR2h-66 (SEQ ID NO: 868), TAR2h-67 (SEQ ID NO: 869), TAR2h-68 (SEQ ID NO: 870) , TAR2h-70 (SEQ ID NO: 871), TAR2h-71 (SEQ ID NO: 872), TAR2h-72 (SEQ ID NO: 873), TAR2h-73 (SEQ ID NO: 874), TAR2h-74 (SEQ ID NO: 875), TAR2h-75 (SEQ ID NO: 876), TAR2h -76 (SEQ ID NO: 877), TAR2h-77 (SEQ ID NO: 878), TAR2h-78 (SEQ ID NO: 879), TAR2h-79 (SEQ ID NO: 880), TAR2h-15 (SEQ ID NO. : 881), TAR2h-131-8 (SEQ ID NO: 882), TAR2h-131-24 (SEQ ID NO: 883), TAR2h-15-8 (SEQ ID NO: 884), TAR2h-15-8-1 (SEQ ID NO: 885), TAR2h-15-8-2 (SEQ ID NO: 886), TAR2h-185-23 (SEQ ID NO: 887), TAR2h-154-10-5 (SEQ ID NO: 888), TAR2h-14-2 (SEQ ID NO: 889), TAR2h-151-8 (SEQ ID NO: 890), TAR2h-152 -7 (SEQ ID NO: 891), TAR2h-35-4 (SEQ ID NO: 892), TAR2h-154-7 (SEQ ID NO: 893), TAR2h-80 (SEQ ID NO: 894), TAR2h-81 (SEQ ID NO: 895), TAR2h-82 (SEQ ID NO: 896), TAR2h-83 (SEQ ID NO: 897), TAR2h-84 (SEQ ID NO: 898), TAR2h-85 (SEQ ID NO: 899), TAR2h-86 (SEQ ID NO: 900), TAR2h-87 (SEQ ID NO: 901), TAR2h-88 (SEQ ID NO: 902), TAR2h -89 (SEQ ID NO: 903), TAR2h-90 (SEQ ID NO: 904), TAR2h-91 (SEQ ID NO: 905), TAR2h-92 (SEQ ID NO: 906), TAR2h-93 (SEQ ID NO: 907), TAR2h-94 (SEQ ID NO: 908), TAR2h-95 (SEQ ID NO: 909), TAR2h -96 (SEQ ID NO: 910), TAR2h-97 (SEQ ID NO: 911), TAR2h-99 (SEQ ID NO: 912), TAR2h-100 (SEQ ID NO: 913), TAR2h-101 (SEQ ID NO : 914), TAR2h-102 (SEQ ID NO: 915), TAR2h-103 (SEQ ID NO: 916), TAR2h-104 (SEQ ID NO: 917), TAR2h-105 (SEQ ID NO: 918), TAR2h-106 (SEQ ID NO: 919), TAR2h-107 (SEQ ID NO: 920), TAR2h -108 (SEQ ID NO: 921), TAR2h-109 (SEQ ID NO: 922), TAR2h-110 (SEQ ID NO: 923), TAR2h-111 (SEQ ID NO: 924), TAR2h-112 (SEQ ID NO : 925), TAR2h-113 (SEQ ID NO: 926), TAR2h-114 (SEQ ID NO: 927), TAR2h-115 (SEQ ID NO: 928), TAR2h-116 (SEQ ID NO: 929), TAR2h-117 (SEQ ID NO: 930), TAR2h-118 (SEQ ID NO: 931), TAR2h-119 (SEQ ID NO: 932), TAR2h-120 (SEQ ID NO: 933), TAR2h-121 (SEQ ID NO: 934), 'TAR2h-122 (SEQ ID NO: 935), TAR2h-123 (SEQ ID NO: 936), TAR2h-124 (SEQ ID NO: 937), TAR2h-125 (SEQ ID NO: 938), TAR2h-126 (SEQ ID NO: 939), TAR2h-127 (SEQ ID NO: 940), TAR2h-128 (SEQ ID NO: 941), TAR2h-129 (SEQ ID NO: 942), TAR2h-130 (SEQ ID NO: 943), TAR2h-131 (SEQ ID NO: 944), TAR2h-132 (SEQ ID NO: 945), TAR2h-133 (SEQ ID NO: 946), TAR2h-151 (SEQ ID NO: 947), TAR2h-152 (SEQ ID NO: 948), TAR2h-153 (SEQ ID NO: 949), TAR2h-154 (SEQ ID NO: 950), TAR2h-159 (SEQ ID NO: 951), TAR2h-165 (SEQ ID NO: 952), TAR2h-166 (SEQ ID NO: 953), TAR2h-168 (SEQ ID NO: 954), TAR2h-171 (SEQ ID NO: 955), TAR2h-172 (SEQ ID NO: 956), TAR2h-173 (SEQ ID NO: 957), TAR2h-174 (SEQ ID NO: 958), TAR2h-176 (SEQ ID NO: 959), TAR2h-178 (SEQ ID NO: 960), TAR2h-201 (SEQ ID NO: 961), TAR2h-202 (SEQ ID NO: 962), TAR2h-203 (SEQ ID NO: 963), TAR2h-204 (SEQ ID NO: 964), TAR2h-185-25 (SEQ ID NO: 965), TAR2h-154-10 (SEQ ID NO: 966), TAR2h-205 (SEQ ID NO: 967), TAR2h-10 (SEQ ID NO: 968), TAR2h-5 (SEQ ID NO: 969), TAR2h-5d1 (SEQ ID NO: 970), TAR2h-5d2 (SEQ ID NO: 971), TAR2h-5d3 (SEQ ID NO: 972), TAR2h-5d4 (SEQ ID NO: 973), TAR2h-5d5 (SEQ ID NO: 974), TAR2h-5d6 (SEQ ID NO: 975), TAR2h-5d7 (SEQ ID NO: 976), TAR2h-5d8 (SEQ ID NO: 977), TAR2h-5d9 (SEQ ID NO: 978), TAR2h-5d10 (SEQ ID NO: 979), TAR2h-5d11 (SEQ ID NO: 980), TAR2h-5d12 (SEQ ID NO: 981), and TAR2h-5d13 (SEQ ID NO: 982). In other embodiments, the ligand comprises a domain antibody monomer (dAb) that specifically binds to the Tumor Necrosis Factor-1 Receptor (TNFR1, p55, CD120a), with a Kd of 300 nM to 5 pM, and comprises an amino acid sequence that is at least about 80 percent, at least about 85 percent, at least about 90 percent, at least about 91 percent, at least about 92 percent, at least about 93 percent, at least about 94 percent, at least about 95 percent, at least about 96 percent, at least about 97 percent, at least about 98 percent, or at least about 99 percent percent homologous to the amino acid sequence or to a dAb selected from the group consisting of TAR2m-14 (SEQ ID NO: 983), TAR2m-15 (SEQ ID NO: 984), TAR2m-19 (SEQ ID N O: 985), TAR2m-20 (SEQ ID NO: 986), TAR2m-21 (SEQ ID NO: 987), TAR2m-24 (SEQ ID NO: 988), TAR2m-21-23 (SEQ ID NO: 989) , TAR2m-21-07 (SEQ ID NO: 990), TAR2m-21-43 (SEQ ID NO: 991), TAR2m-21-48 (SEQ ID NO: 992), TAR2m-21-10 (SEQ ID NO: 993), TAR2m-21-06 (SEQ ID NO: 994), and TAR2m-21-17 (SEQ ID NO: 995).
In some embodiments, the ligand comprises a dAb monomer that binds to TNFR1, and competes with any of the dAbs disclosed herein for binding to TNFR1 (e.g., mouse and / or human TNFR1) dAbs Resistant to Protease. The invention also relates to dAb monomers that are resistant to degradation by the protease (e.g., septa protease, cysteine protease, matrix metalloprotease, pepsin, trypsin, elastase, chymotrypsin, carboxypeptidase, cathepsin (eg, cathepsin G), protemase 3), and ligands that comprise a protease resistant dAb. proteases (eg, a septa protease, cysteine protease, matrix metalloprotease) function in the normal metabolism and change of proteins. However, in certain physiological states, such as inflammatory states (eg, chronic obstructive pulmonary disease) and in cancer, the amount of proteases present in a tissue, organ, or animal (e.g., in the lung, within or adjacent to a tumor) may increase. This increase in proteases may result in accelerated degradation and inactivation. of the endogenous proteins and the peptides, polypeptides, and therapeutic proteins that are administered In fact, some agents have the potential to be used in vivo (eg example, to be used in the treatment, diagnosis, or prevention of the disease), they have only limited effectiveness, because they are quickly degraded and inactivated by proteases. The invention relates to a dAb or a ligand comprising a dAb that is resistant to degradation by the protease. The protease resistant dAbs of the invention provide several advantages. For example, a protease resistant dAb can be administered to a subject and can remain active in vivo for longer than protease sensitive agents. In accordance with the above, the protease resistant dAbs will remain functional for a period of time that is sufficient to produce biological effects. A dAb that is resistant to degradation by the protease is not substantially degraded by a protease when incubated with the protease under conditions suitable for protease activity for at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours , at least about 24 hours, at least about 36 hours, or at least about 48 hours. A dAb is not substantially degraded when not more than about 25 percent, no more than about 20 percent, no more than about 15 percent, no more than about 14 percent, no more than about 13 percent, no more than about 12 percent, no more than about 11 percent, no more than about 10 percent , no more than about 9 percent, no more than about 8 percent, no more than about 7 percent, no more than about 6 percent, no more than about 5 percent, no more than about 4 percent, no more than about 3 percent, no more than about 2 percent, no more than about 1 percent, or substantially none of the protein is degraded by the protease after incubation with the protease during at least about 2 hours. The degradation of the protein can be evaluated using any suitable method, for example, by SDS-PAGE, as described herein. The resistance to the protease can be evaluated using any suitable method. For example, a protease may be added to a solution of dAb in a suitable regulator (eg, phosphate buffered serum), to produce a solution of dAb / protease, such as a solution of at least about 0.01 percent (weight / weight) of protease, from about 0.01 percent to about 5 percent (w / w) of protease, from about 0.05 percent to about 5 percent (w / w) of protease, of about 0.1 percent to about 5 percent percent (weight / weight) of protease, from about 0 5 percent to about 5 percent (w / w) of protease, from about 1 percent to about 5 percent (w / w) of protease, from at least about 0 01 (weight / weight) of protease, from at least about 0 02 percent (w / w) of protease, from at least about 0 03 (w / w) of protease, at least about 0 04 (weight / weight) of protease, from at least about 0 05 (w / w) of protease, from at least about 0 06 (w / w) of protease, from at least about 0 07 ( weight / weight) of protease, from at least about 0 08 (weight / weight) of protease, from at least about 0 09 (weight / weight) of protease, from at least about 0 1 (weight / weight) of protease, at least about 0 2 percent (w / w) of protease, from at least about 0 3 (w / w) of protease, from at least about 0 4 (w / w) of protease, from at least about 0 5 (w / w) of protease, from at least about 0 6 (w / w) of protease, from at least about 0 7 (w / w) of protease, from at least about 0 8 (w / w) of protease, to at least about 0 9 (w / w / weight) of protease, from at least about 1 percent (w / w) of protease, of at least about 2 (w / w) of protease, of at least about 3 (w / w) of protease, at least about 4 (w / w) protease, or at least about 5 (w / w) protease. The dAb / protease mixture can be incubated at a temperature suitable for protease activity (e.g., at 37 ° C), and samples can be taken at time intervals (e.g., at 1 hour, 2 hours, 3 hours). hours, etc.), and the protease reaction stops. The samples can then be analyzed to determine the degradation of the protein using any suitable method, such as an SDS-PAGE analysis. The results can be used to establish a degradation time course. In particular embodiments, the protease resistant dAb is resistant to degradation by elastase. For example, the elastase-resistant dAb is not substantially degraded when incubated at 37 ° C in a 0.04 percent (w / w) elastase solution for a period of at least about 2 hours. Preferably, the elastase-resistant dAb is not substantially degraded when incubated at 37 ° C in a 0.04 percent (w / w) elastase solution for a period of at least about 12 hours. More preferably, the elastase-resistant dAb is not substantially degraded when incubated at 37 ° C in a 0.04 percent (w / w) elastase solution for a period of at least about 24 hours, at least about 36 hours, or at least about 48 hours.
In particular embodiments, the protease resistant dAb is resistant to degradation by trypsin. For example, trypsin-resistant dAb is not substantially degraded when incubated at 37 ° C in a 0.04 percent (w / w) solution of trypsin, for a period of at least about 2 hours. Preferably, the trypsin-resistant dAb is not substantially degraded when incubated at 37 ° C in a 0.04 percent (w / w) solution of trypsin for a period of at least about 3 hours. More preferably, the trypsin-resistant dAb is not substantially degraded when incubated at 37 ° C in a 0.04 percent (w / w) solution of trypsin for a period of at least about 4 hours, of at least about 5 hours , from at least about 6 hours, from at least about 7 hours, from at least about 8 hours, from at least about 9 hours, of at least about 10 hours, of at least about 11 hours, or of at least about 12 hours . In certain embodiments, the invention does not include TAR1-5-19 disclosed in International Publication Number WO 2004/081026. Preferably, the protease resistant dAb is a light chain variable domain. For example, the protease resistant dAb may be a VK or a V ?.
The protease resistance of the dAbs can be correlated with the melting temperature (Tm) of the dAbs. Generally speaking, a higher melting temperature correlates with resistance to the protease. In some embodiments, the protease resistant dAb has a Tm of between about 40 ° C and about 95 ° C, between about 40 ° C and about 85 ° C, from about 40 ° C to about 80 ° C, from about 45 ° C to about 95 ° C, from about 45 ° C to about 85 ° C, from 45 ° C to about 80 ° C, at least about 40 ° C, from at least about 45 ° C, from at least about 50 ° C, from at least about 55 ° C, from at least about 60 ° C, from at least about 65 ° C, from at least about 70 ° C, of at least about 75 ° C, of at least about 80 ° C, of at least about 85 ° C, of at least about 90 ° C, or of at least about 95 ° C The dAb resistant to protease can of having binding specificity for any desired target, such as human or animal proteins, including cytokines, growth factors, cytokine receptors, growth factor receptors, enzymes (e.g., proteases), co-factors for enzymes and proteins of binding of DNA, lipids, and carbohydrates. The objectives Suitable proteins, including cytokines, growth factors, cytokine receptors, growth factor receptors, and other proteins, include, but are not limited to ApoE, Apo-SAA, BDNF, Card? otrof? na-1, CEA, CD40 , Ligand of CD40, CD56, CD38, CD138, EGF, EGF receptor, ENA-78, Eotaxma, Eotax? Na-2, Exodus-2, FAPa, FGF-acid, FGF-basic, f? Broblast growth factor -10, FLT3 ligand, Fractalqume (CX3C), GDNF, G-CSF, GM-CSF, GF-β1, human serum albumin, insulin, IFN- ?, IGF-I, IGF-II, IL-1a, I L-1 ß, IL-1 receptor, IL-1 receptor type 1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8 (72 amino acids) , IL-8 (77 amino acids), IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18 (IGIF), Inhibin a , Inhibin ß, IP-10, keratinocyte growth factor-2 (KGF-2), KGF, Leptin, LIF, lymphotactin, inhibitor substance Mullepana, monocyte colony inhibitory factor, monocyte-attracting protein, M -CSF, MDC (67 amino acids), MDC (69 amin) oacids), MCP-1 (MCAF), MCP-2, MCP-3, MCP-4, MDC (67 amino acids), MDC (69 amino acids), MIG, MIP-1a, MIP-1β, MIP-3a, MIP- 3ß, MIP-4, progenitor inhibitor m? Elo? De-1 (MPIF-1), NAP-2, Neurtupna, nerve growth factor, ß-NGF, NT-3, NT-4, Oncostatma M, PDGF-AA, PDGF-AB, PDGF-BB, PF-4, RANTES, SDF1a, SDF1β, SCF, SCGF, totipotent cell factor (SCF), TARC, TGF-α, TGF-β, TGF-β2, TGF- β3, tumor necrosis factor (TNF), TNF-α, TNF-β, TNF receptor I, TNF receptor II, TNIL-1, TPO, VEGF, VEGF A, VEGF B, VEGF C, VEGF D, VEGF receptor -1, VEGF-2 receptor, VEGF-3 receptor, GCP- 2, GRO / MGSA, GRO-β, GRO- ?, HCC1, 1-309, HER 1, HER 2, HER 3, HER 4, serum albumin, vWF, amyloid proteins (eg, alpha-amyloid), MMP12 , PDK1, IgE, and other objects disclosed herein. It will be appreciated that this list is by no means exhaustive. In some embodiments, protease resistant dAbs bind to a target in the lung tissue, such as a targeted target. from the group consisting of TNFR1, IL-1, IL-1R, IL-4, IL-4R, IL-5, IL-6, IL-6R, IL-8, IL-8R, IL-9, IL- 9R, IL-10, IL-12, IL-12R, IL-13, IL-13Ra1, IL-13Ra2, IL-15, IL-15R, IL-16, IL-17R, IL-17, IL-18, IL-18R, IL-23, IL-23R, IL-25, CD2, CD4, CD11a, CD23, CD25, CD27, CD28, CD30, CD40, CD56, CD56, CD138, ALK5, EGFR, FcER1, TGFb, CCL2, CCL18, CEA, CR8, CTGF, CXCL12 (SDF-1), chymase, FGF, Fupna, Endotel? Na-1, Eotaxins (for example, Eotaxin, Eotax? Na-2, Eotax? Na-3), GM-CSF , ICAM-1, ICOS, IgE, IFNa, 1-309, integpnas, L-selectin, MIF, MIP4, MDC, MCP-I, MMPs, neu elastase trophiles, osteopontin, OX-40, PARC, PD-1, RANTES, SCF, SDF-I, siglec, TARC, TGFb, Thrombin, T? m-1, TNF, TRANCE, Tpptase, VEGF, VLA-4, VCAM, a4β7, CCR2, CCR3, CCR4, CCR5, CCR7, CCR8, alphavbetad, alphavbetad, cMET, CD8, vWF, amyloid proteins (eg, alpha-amyloid), MMP12, PDK1, and IgE The protease resistant dAbs of the invention can be administered m alive, and will remain functional for longer than compounds that are not similarly resistant to degradation by the protease A dAb of the invention that is resistant to degradation by the protease can be used for the treatment of an inflammatory disease (eg, by local delivery to the lung by pulmonary administration, for example by intranasal administration , eg by inhalation) For example, by administering to a subject in need, a therapeutically effective amount of a dAb monomer that is resistant to degradation by the protease The invention also relates to a dAb monomer that is resistant to degradation by the protease for use in therapy, diagnosis, and / or prophylaxis, and to the use of this dAb monomer of the invention for the manufacture of a medicament of a disease described herein (e.g., an inflammatory disease, arthritis, a respiratory disease) In particular modalities, the protease resistant dAb monomer can be used for the treatment of an inflammatory disease, arthritis, or a respiratory disease, by pulmonary administration. The protease resistant dAb monomer can also be used in the manufacture of a medicament for the treatment of an inflammatory disease, arthritis, or a respiratory disease, wherein the dAb monomer is administered by pulmonary administration. Elastase and trypsin are the most common proteases found in the lung. Preferably, the protease resistant dAbs for pulmonary administration they are resistant to elastase, resistant to trypsin, or resistant to elastase and resistant to trypsin. In particular embodiments, the protease resistant dAb monomer (e.g., the elastase resistant dAb monomer) binds to IL-1R1, and inhibits the binding of IL-1 (e.g., IL-1a and / or I L-1 ß) with the receptor, but does not inhibit the binding of IL-1ra with IL-1R1, and with ligands comprising these dAb monomers. These dAb monomers are useful as therapeutic agents for the treatment of inflammation, diseases or other conditions mediated in whole or in part by the biological functions induced by the binding of IL-1 with IL-1R1 (eg, local or systemic inflammation). , elaboration of inflammatory mediators (for example, I L-6, IL-8, TNF), fever, cells immune to activation (for example, lymphocytes, neutrophils), anorexia, hypotension, leukopenia, thrombocytopenia). The protease-resistant dAb monomers can bind to I L-1 R 1 and inhibit the function of IL-1R1 without interfering with the endogenous IL-1R1 inhibitory pathways, such as the endogenous I L-1 ra linkage. with endogenous IL-1R1. Accordingly, this dAb monomer can be administered to a subject to complement the endogenous regulatory pathways that inhibit the activity of IL-1R1 or of living IL-1 m In addition, the protease-resistant dAb monomers that are link to IL-1R1 and do not inhibit the binding of I L-1 ra with IL-1R1, provide advantages to be used as agents of diagnosis, because they can be used to link and detect, quantify or measure IL-1R1 in a sample, and will not compete with IL-Ira in the sample for binding to IL-1R1. Accordingly, an accurate determination can be made as to whether there is or how much I L-1 R 1 is in the sample. The protease-resistant dAb monomers (e.g. elastase-resistant dAb monomers that bind to IL-1R1, and that inhibit the binding of IL-1 (for example, IL-1a and / or I L-1β) with the receptor, but do not inhibit the binding of I L-1 ra with IL- 1R1, are also useful research tools. For example, this dAb monomer can be used to identify agents (eg, other dAbs, small organic molecules) that bind to IL-1R1, but do not inhibit IL-1 binding. Ira with IL-1R1 In an illustrative example, an agent or a collection of agents to be tested for their ability to inhibit the binding of IL-1R to IL-1R1, are tested in a binding assay competitive L-1 R 1 receptor, such as the receptor binding assay described herein.The agents that inhibit the IL-1 with IL-1R1 in this assay can then be studied in a similar competitive L-1 R 1 receptor binding assay, to see if they compete with a dAb monomer that binds to IL-1R1 , but does not inhibit the binding of IL-1ra with IL-1R1 The competitive binding in this assay indicates that the agent binds to IL-1R1, and inhibits the binding of IL-1 to the receptor, but does not inhibit the Link of I L- 1 ra with the receiver In some embodiments, the protease resistant dAb binds to the IL-1R1, and competes with any of the dAbs disclosed herein, for the linkage with the IL-1R1 (e.g., the I L-1 R 1 human). In some embodiments, the dAb is resistant to at least elastase and / or trypsin. In other embodiments, the protease resistant dAb competes p) or < r the binding to IL-1R1, with an anti-IL-1R1 dAb, wherein the anti-l L-1 R 1 dAb comprises an amino acid sequence that is at least about 80 percent, at least about 85 percent, at least about 90 percent, at least about 911 percent, at least about 92 percent, at least about 93 percent, at least about 94 percent, at least about 95 percent, at least about 96 percent, at least about 97 percent, at least about 98 percent, or at least about 99 percent homologous to the amino acid sequence or to a dAb selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 349. In other embodiments, the protease resistant dAb competes for binding to IL-1R1, with an anti-L-1 R 1 dAb, wherein the anti-l L-1 R 1 dAb comprises an amino acid sequence that is at least about 80 percent, at least about 85 percent, at least about 90 percent, at least about 91 percent, at least about 92 percent, at least about 93 percent, at least about 94 percent, at least about 95 percent, at least about 96 percent, at least about 97 percent, at least about 98 percent, or at least about 99 percent homologous to the amino acid sequence or a dAb selected from the group consisting of SEQ ID NO: 1 or SEQ ID NO: 2. In other embodiments, the protease-resistant dAb competes for binding with IL-1R1, with an anti-IL-1 R 1 dAb, wherein the anti-l L-1 R1 dAb comprises an amino acid sequence that is when less about 80 percent, at least about 85 percent, at least about 90 percent, at least about 91 percent, at least about 92 percent, at least about 93 percent, at least ap approximately 94 percent, at least approximately 95 percent, at least approximately 96 percent, at least approximately 97 percent, at least approximately 98 percent, or at least approximately 99 percent homologous to amino acid sequence or a dAb selected from the group consisting of SEQ ID NO: 3 to SEQ ID NO: 7.
In other embodiments, the protease resistant dAb competes for the linkage with the IL-1R1, with an anti-l L-1 R 1 dAb, wherein the anti-l L-1 R 1 dAb comprises the amino acid sequence DOM4 -130-54 (SEQ ID NO: 7), or an amino acid sequence that is at least about 80 percent, at least about 85 percent, at least about 90 percent, at least about 91 percent , at least about 92 percent, at least about 93 percent, at least about 94 percent, at least about 95 percent, at least about 96 percent, at least about 97 percent, when at least about 98 percent, or at least about 99 percent homologous to DOM4-130-54 (SEQ ID NO: 7). Ligand Formats The ligands and monomers of dAb can be formatted as mono- or multi-specific antibodies, or as fragments of antibodies, or in structures that are not mono- or multi-specific antibodies. Suitable formats include any suitable polypeptide structure wherein an antibody variable domain or one or more of the complementarity determining regions thereof can be incorporated, to confer specificity of binding by the antigen on the structure. A variety of suitable antibody formats are known in the art, such as IgG type formats, chimeric antibodies, humanized antibodies, human antibodies, single-chain antibodies, bispecific antibodies, heavy chains of antibodies, light chains of antibodies, homodimers and heavy chain heterodimers and / or light chains of antibodies, antigen binding fragments of any of the foregoing (for example, a Fv fragment (e.g., single chain Fv (scFv), a disulfide linked Fv), a Fab fragment, a Fab 'fragment, a F (ab') 2 fragment), a single variable domain (e.g. VH, V, VHH), a dAb, and modified versions of any of the foregoing (e.g., modified by the covalent attachment of polyalkylene glycol (e.g., polyethylene glycol, polypropylene glycol, polybutylene glycol), or other suitable polymer). See TCP Publication PCT Number / GB03 / 002804, filed June 30, 2003, which designated the United States (International Publication Number WO 2004/081026) with respect to the only PEGylated variable domains and dAbs, the methods suitable for their preparation, the longer half-life in vivo of the only PEGylated variable domains, and monomers and multimers of dAb, suitable PEGs, preferred hydrodynamic sizes of the PEGs, and preferred hydrodynamic sizes of the only PEGylated variable domains and the monomers and multimers of dAb. All teaching of the PCT Publication Number PCT / GB03 / 002804 (International Publication Number WO 2004/081026), including the portions referred to above, is incorporated herein by reference. The ligand can be formatted as a dimer, trimer, or polymer of a desired dAb monomer, for example, using a suitable linker, such as (Gly Ser) n, where n = from 1 to 8, for example 2, 3, 4, 5, 6, or 7 If desired The ligands, including monomers, dimers, and dAb trimers, can be linked to an antibody Fe region, which comprises one or both of the CH2 and CH3 domains, and optionally a joint region. For example, vectors can be used. which encode ligands linked as a single nucleotide sequence to an Fe region to prepare these polypeptides. The dAb ligands and monomers can also be combined and / or formatted into multiple non-antibody structures to form multivalent complexes, which bind to the target molecules, thus providing superior avidity. For example, using natural bacterial receptors such as SpA as scaffolds for the grafting of complementarity determining regions, in order to generate ligands that specifically bind with one or more epitopes. Details of this procedure are described in the US Pat. US No. 5,831,012 Other suitable scaffolds include those based on fibronectm and afibodies. Details of suitable procedures are described in International Publication Number WO 98/58965 Other suitable scaffolds include lipocalm and CTLA4, as described in van den Beuken et al., J Mol Biol 310591-601 (2001), and the scaffolds such as those described in International Publication Number WO 00/69907 (Medical Research Council), which are based, for example, on the ring structure of the bacterial GroEL or other chaperone polypeptides. The protein scaffolds can be combined; for example, the complementarity determining regions can be grafted onto a CTLA4 scaffold, and can be used in conjunction with the immunoglobulin VH or VL domains to form a ligand. In the same way, fibronectin, pochaline, and other scaffolds may be combined. A variety of methods suitable for the preparation of any desired format are known in the art. For example, chains and formats of antibodies can be prepared (eg, IgG-like formats, chimeric antibodies, humanized antibodies, human antibodies, single-chain antibodies, bispecific antibodies, heavy chains of antibody, light chains of antibody, or homodimers and heavy chain heterodimers and / or light chains of antibodies), by expressing suitable expression constructs and / or suitable cell cultures (e.g., hibpdomas, hetero-hibpdomas, recombinant host cells containing recombinant constructs encoding the format) In addition, formats such as antibody antigen binding fragments or antibody chains (eg, a Fv fragment (eg, single chain Fv (scFv), disulfide linked Fv), a Fab fragment can be prepared. , a Fab 'fragment, a fragment F (ab ') 2), by expression of suitable expression constructs, or by enzymatic digestion of the antibodies, for example using papain or pepsin. The ligand can be formatted as a specific double ligand or as a multispecific ligand, for example , as described in International Publication Number WO 03/002609, the total teachings of which are incorporated herein by reference. The specific double ligands comprise unique immunoglobulm variable domains having different binding specificities. These specific double bonds may comprise combinations of heavy and light chain domains For example, the double specific ligand may comprise a VH domain and a V domain, which may be linked together in the form of a scFv (e.g., using a suitable linker, such as Gly Ser ), or they can be formatted in a bispecific antibody or an antigen binding fragment of my smo (for example, fragment F (ab ') 2) The specific double ligands do not comprise pairs of VH / V | Complementary sites that form a conventional two-chain antibody antigen binding site that binds the antigen or epitope in a cooperative manner. Instead, the double-format ligands comprise a complementary VH / VL pair, wherein the V domains they have different binding specificities In addition, the specific double gandos may comprise one or more CH or CL domains, if desired. it may include a joint region domain if desired. These combinations of domains, for example, may mimic natural antibodies, such as IgG or IgM, or fragments thereof, such as Fv, scFv, or F (ab ') 2 molecules. Other structures are envisaged, such as a single arm of an IgG molecule comprising the VH, VL, VH1, and CL domains. Preferably, the double specific ligand of the invention comprises only two variable domains, although several of these ligands can be incorporated together in the same protein, for example, two of these ligands can be incorporated into an IgG or a multimeric immunoglobulin. , such as IgM. Alternatively, in another embodiment, a plurality of specific double ligands are combined to form a multimer. For example, two different double specific ligands are combined to create a tetra-specific molecule. One skilled in the art will appreciate that the variable regions liberate and weigh a double specific ligand produced according to the method of the invention, may be on the same polypeptide chain, or alternatively, on different polypeptide chains. If the variable regions are on different polypeptide chains, then they can be linked by means of a linker, generally a flexible linker (such as a polypeptide chain), a chemical linker group, or any other method known in this field. Multispecific ligand possesses more than one specificity of epitope binding In general terms, the multispecific ligand comprises two or more epitope-binding domains, such as dAbs or a non-antibody protein domain comprising a binding site for an epitope, for example, an affinity, a SpA domain, an LDL class A receptor domain, an EGF domain, an avimero domain. The multispecific ligands can be further formatted as described herein. In some embodiments, the ligand is in an IgG type format. These formats have the conventional structure of four chains of one molecule of IgG (two heavy chains and two light chains), where one or more of the variable regions (VH and VL) have been replaced with a dAb or with a single variable domain of a desired specificity Preferably, each of the variable regions (two VH regions and two VL regions) is replaced with a dAb or with a single variable domain The dAb (s) or the only variable domains that are included in a standard format IgG may have the same specificity or different specificities In some embodiments, the IgG type format is tetravalent, and may have one, two, three, or four specificities. For example, the IgG type format may be monospecific, and comprises four dAbs that have the same specificity, bispecific, and comprises three dAbs that have the same specificity and another dAb that has a different, bispecific specificity and comprises two dAbs that have the same specificity and two dAbs that have a common specificity but different, specific and comprises first and second dAbs that have the same specificity, a third dAb with a different specificity, and a fourth dAb with a different specificity from the first, second, and third dAbs, or tetraespecific and comprises four dAbs that have each one a different specificity Antigen binding fragments of IgG-like formats (eg, Fab, F (ab ') 2, Fab', Fv, scFv) can be prepared Preferably, the IgG type formats or the binding fragments of antigen do not cross-link the TNFR1 Formats that prolong the half-life. The ligand, such as a dAb monomer, can be formatted to prolong its serum half life in vivo. The longer half-life in vivo is useful in the in vivo applications of immunoglobulms, especially antibodies, and more especially antibody fragments. small size, such as dAbs These fragments (Fvs, Fvs linked by disulfide, Fvs, Fabs, scFvs, dAbs) are rapidly eliminated from the body, which may limit clinical applications Small gandos, such as a dAb monomer, can be formatted as a larger antigen binding fragment of an antibody, or as an antibody (eg, formatted as a Fab, Fab ', F (ab) 2, F (ab') 2, IgG, scFv) A ligand (eg example, a dAb monomer) can be formatted as a larger antigen binding fragment of an antibody, or as an antibody (for example, it can be formatted as a Fab, Fab ', F (ab) 2, F (ab') 2, IgG, scFv) having a larger hydrodynamic size Ligands can also be formatted to have a larger hydrodynamic size, for example, by binding of a polyalkylene glycol group (eg, a polystyrene glycol group (PEG), polypropylene glycol, polybutylene glycol), serum albumin, transferpna, transferpna receptor, or at least the transferpna binding portion thereof, an antibody Fe region , or by conjugation with an antibody domain In some embodiments, the ligand (e.g., the dAb monomer) is PEGylated. Preferably, the PEGylated ligand (e.g., the dAb monomer) is linked to the I L -1R 1 with substantially the same affinity as the same ligand that is not PEGylated For example, the ligand may be a PEGMED dAb monomer that binds to IL-1R1, where the monomer of PEGylated dAb binds to the IL -1R1 with an affinity that differs from e the affinity of the dAb in a non-PEGylated form, by not more than a factor of about 1,000, preferably not more than a factor of about 100, more preferably not more than a factor of about 10, or with a substantially unchanged affinity in relation to the non-PEGylated form See TCP Publication Number PCT / GB03 / 002804, filed on June 30, 2003, which designates the United States (International Publication Number WO 2004/081026), regarding the PEGilation of the only variable domains and dAbs, the right methods for their preparation, the longer life in vivo media of the only PEGylated variable domains and the monomers and multimers of dAb, the appropriate PEGs, the preferred hydrodynamic sizes of the PEGs, and the preferred hydrodynamic sizes of the only PEGylated variable domains and dAb monomers and multimers. All teaching of the PCT Publication Number PCT / GB03 / 002804 (International Publication Number WO 2004/081026), including the portions referred to above, is incorporated herein by reference. The hydrodynamic size of the derivatives (e.g., dAb monomers and multimers) of the invention can be determined using methods that are well known in the art. For example, gel filtration chromatography can be used to determine the hydrodynamic size of a ligand. Gel filtration matrices suitable for determining the hydrodynamic sizes of the ligands, such as cross-linked agarose matrices, are well known and readily available. The size of a ligand format (eg, the size of a PEG moiety bound to a monomer of dAb) can be varied depending on the desired application. For example, when the ligand is intended to leave the circulation and enter peripheral tissues, it is desirable to maintain the hydrodynamic size of the ligand low to facilitate extravasation from the bloodstream. Alternatively, when it is desired to cause the ligand to remain in the systemic circulation for a longer period of time, the ligand size can be increased, by 14 example, by formatting as an Ig-like protein, or by the addition of a PEG fraction of 30 to 60 kDa (eg, linear or branched PEG 30 up to 40 kDa PEG, such as the addition of two PEG fractions of 20 kDa). The hydrodynamic size of a ligand (e.g., dAb monomer) and its serum half-life can also be increased by conjugation or binding of the ligand to a binding domain (e.g., antibody or antibody fragment) that is linkage with an antigen or epitope that increases the half-life in vivo, as described herein. For example, the ligand (e.g., the dAb monomer) can be conjugated or linked to an antibody or a neonatal Fe antibody or antireceptor fragment, e.g., a dAb, Fab, Fab ', or anti-albumin or antiviral scFv. Neonatal Fe receptor, or with an anti-serum albumin affinity or with an anti-neonatal Fe receptor affinity. Examples of albumin, albumin fragments, or albumin variants suitable for use in a ligand according to the invention are described in International Publication Number WO 2005 / 077042A2, which is incorporated herein by reference in its entirety. In particular, the following albumins, albumin fragments, or albumin variants can be used in the present invention: • SEQ ID NO: 1 (as disclosed in International Publication Number WO 2005 / 077042A2, this sequence being incorporated explicitly to the present disclosure by reference); Fragment or variant of albumin comprising or consisting of amino acids 1 to 387 of SEQ ID NO: 1 of International Publication Number WO 2005 / 077042A2; • Albumin, or fragment or variant thereof, comprising an amino acid sequence selected from the group consisting of: (a) amino acids 54 to 61 of SEQ ID NO.1 of International Publication Number WO 2005 / 077042A2 , (b) amino acids 76 to 89 of SEQ ID NO 1 of International Publication Number WO 2005 / 077042A2; (c) amino acids 92 to 100 of SEQ ID NO of International Publication Number WO 2005 / 077042A2, (d) amino acids 170 to 176 of SEQ ID NO: 1 of International Publication Number WO 2005 / 077042A2; (e) amino acids 247 to 252 of SEQ ID NO 1 of International Publication Number WO 2005 / 077042A2, (f) amino acids 266 to 277 of SEQ ID No. 1 of International Publication Number WO 2005 / 077042A2; (g) amino acids 280 to 288 of SEQ ID NO of International Publication Number WO 2005 / 077042A2, (h) amino acids 362 to 368 of SEQ ID NO: 1 of International Publication Number WO 2005 / 077042A2, (i) ) amino acids 439 to 447 of SEQ ID NO. of International Publication Number WO 2005 / 077042A2, (j) amino acids 462 to 475 of SEQ ID NO 1 of International Publication Number WO 2005 / 077042A2; (k) amino acids 478 to 486 of SEQ ID NO I of International Publication Number WO 2005 / 077042A2, and (I) amino acids 560 to 566 of SEQ ID NO: 1 of International Publication Number WO 2005 / 077042A2 Other examples of albumins, fragments, and analogs suitable for use in a ligand according to the invention are described in International Publication Number WO 2005 / 077042A2, which is incorporated herein by reference in its entirety. In particular, the following albumins, fragments, or variants may be used in the present invention • Human serum albumin as described in International Publication Number WO 03 / 076567A2, for example in Figure 3 (this sequence information being incorporated explicitly to the present disclosure by reference); • Human serum albumin (HA), which consists of a single non-glycosylated polypeptide chain of 585 amino acids, with a molecular weight of the formula of 66,500 (see Meloun, et al., FEBS Letters 58. 136 (1975); Behrens, et al., Fed. Proc. 34,591 (1975), Lawn, et al., Nucleic Acids Research 96102-6114 (1981), Minghetti, et al., J. Biol Chem.261.6141 (1986)); • A polymorphic variant or an analog or fragment of albumin, as described in Weitkamp, and collaborators, Ann Hum. Genet 37219 (1973), • A fragment or variant of albumin as described in European Patent Number EP 322094, for example HA (1-373, HA (1-388), HA (1-389), HA (1- 369), and HA (1-419), and the fragments between 1-369 and 1-419; 17 • A fragment or variant of albumin as described in European Patent Number EP 399666, for example HA (1-177) and HA (1-200), and fragments between HA (1-X), wherein X is any number from 178 to 199. When one (one or more) fraction that extends the half-life (eg, albumin, transferpna, and fragments and analogs thereof) is used in the derivatives of the invention, it can be conjugated using any suitable method, such as by direct fusion with the binding moiety of IL-1R1 (e.g., dAb or anti-IL-1 R1 antibody fragment (e.g., using a single nucleotide construct encoding a fusion, wherein the fusion protein is encoded as a single polypeptide chain with a fraction that extends the N- or C-terminally localized half-life for the binding fraction of IL-1R1. Alternatively, the conjugation is can be achieved using a peptide linker and Among the fractions, for example, a peptide linker as described in International Publication Number WO 076567A2 or International Publication Number WO 2004/003019 (these linker disclosures are incorporated by reference to the present disclosure to provide Examples for use in the present invention). Typically, a polypeptide that improves serum half-life in vivo, is a polypeptide that naturally occurs m vivo, and that resists degradation or removal by mechanisms endogenous substances that remove unwanted material from the organism (eg, human) For example, a polypeptide that improves the serum half-life in vivo, can be selected from extracellular matrix proteins, the proteins found in the blood, the proteins found in the blood-brain barrier, or in the neural tissue, the proteins located in the kidney, liver, lung, heart, skin, or bone, the proteins of tension, the specific proteins of diseases, or the proteins involved in the transport of Fe Suitable polypeptides that improve the half-life in serum m vivo include, for example, the ligand-neuropharmaceutical agent-specific proteins of the transferpna receptor (see U.S. Patent No. 5,977,307 , the teachings of which are incorporated herein by reference), the brain capillary endothelial cell receptor, transferpna, receptor of transferpna (eg, soluble transferpna receptor, insulin, growth factor receptor type nsul? na-1 (IGF-1), growth factor receptor? nsul? na-2 (IGF-2), receptor of insulin, blood coagulation factor X, a1 -antitppsma, and HNF-1a Suitable polypeptides that improve serum half-life also include glycoprotein alpha-1 (orosomucoid, AAG), anti-chymotrypsin alfa-1 (ACT), alpha microglobulin -1 (HC protein; AIM), antithrombin III (AT III), apolipoprotein A-1 (Apo A-1), apolipoprotein B (Apo B), ceruloplasmin (Cp), complement component C3 (C3), 19 complement component C4 (C4), C1 esterase inhibitors (C1 INH), C-reactive protein (CRP), ferptin (FER), hemopex (HPX), lipoprotein (a) (Lp (a)), protein binding mañosa (MBP), myoglobin (Myo), prealbumin (transpiretma, PAL), retinol binding protein (RBP), and rheumatoid factor (RF). Suitable proteins from the extracellular matrix include, for example, collagens, lammins, integpins, and fibronectin. Collagens are the major proteins of the extracellular matrix. Currently, approximately 15 types of collagen molecules are known, which are found in different parts of the body, for example type I collagen (which accounts for 90 percent of body collagen (found in bone, skin, tendon, ligaments, cornea). , internal organs, or type II collagen found in cartilage, spinal disc, notochord, and vitreous humor of the eye, suitable proteins in the blood include, for example, plasma proteins (eg, fibrin, α-2 macroglobulm , serum albumin, fibpnogen (eg, fibpnogen A, fibpnogen B), serum amyloid protein A, haptoglobin, profilin, ubiquitme, uteroglobulin, and β-2 microglobulin), enzymes, and enzyme inhibitors (eg, plasminogen, lysozyme) , cystatin C, anti-tppsin alfa-1, and pancreatic trypsin inhibitor), immune system proteins, such as immunoglobulin proteins (eg, IgA, IgD, IgE, IgG, IgM, immunoglobulin light chains (kappa / lambda)), proteins from transport (eg, retinol binding protein, α-1 microglobu), defenses (eg, beta-defensin 1, neutrophil defensive 1, neutrophil defensin 2, and neutrophil defensin 3, and the like). which are in the blood brain barrier or neural tissue include, for example, melanocortic receptor, myelin, ascorbate transporter, and the like. Suitable polypeptides that improve the half-life in live serum also include proteins located in the kidney. (eg, polycystin, type IV collagen, K1 organic anion transporter, Heymann antigen), proteins located in the liver (eg, alcohol dehydrogenase, G250), proteins located in the lung (eg, secretory component) , which binds to IGA), the proteins located in the heart (for example, HSP27, which is associated with dilated cardiomyopathy), proteins located in the skin (eg, keratum), bone-specific proteins, such as morphogenic proteins (BMPs), which are a subset of the super-family of proteins of transforming growth factor β, which demonstrate osteogenic activity (eg, BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8), tumor-specific proteins (eg, antigen) of trophoblasts, herceptin receptor, estrogen receptor, cathepsins (for example, cathepsin B, which can be found in the liver and spleen) Suitable disease-specific proteins include, for example, antigens that are expressed only on activated T-cells, including LAG-3 (hnfocyte activation gene), osteoprotective ligand (OPGL, see Nature 402, 304-3309 ( 1999)), OX40 (a member of the family of TNF receptors, expressed on activated T-cells, and specifically amplified in the cells producing human type I T-cell leukemia virus (HTLV-I); Immunol. 165 (1) 263-70 (2000)). Suitable disease-specific proteins also include, for example, metalloproteases (associated with arthritis / cancers), including Drosophila CG6512, human paraplegina, human FtsH, human AFG3L2, mupno FtsH, and angiogenic growth factors, including human growth factor. acid fibroblasts (FGF-1), basic fibroblast growth factor (FGF-2), vascular endotehal growth factor / vascular permeability factor (VEGF / VPF), transforming growth factor-a (TGF-a), tumor necrosis-a (TNF-a), angiogenin,? nterleuc? na-3 (IL-3),? nterleuc? na-8 (IL-8), platelet-derived endothelial growth factor (PD-ECGF), factor of placental growth (PIGF), growth factor derived from platelets of midquina-BB (PDGF), and fractalquma. Suitable polypeptides that improve serum half-life in vivo also include strain proteins, such as heat shock proteins (HSPs). Heat shock proteins are usually found intracellularly. When find extracellularly, this is an indicator that a cell has died and has spilled its contents outward. This unscheduled cell death (necrosis) occurs when, as a result of trauma, disease, or injury, extracellular heat shock proteins trigger a response from the immune system. Linkage to the extracellular heat shock protein may result in localization of the compositions of the invention at a disease site. Suitable proteins involved in the transport of Fe include, for example, the Brambell receptor (also known as FcRB). ). This Fe receptor has two functions, both of which are potentially useful for the supply. The functions are- (1) transport of IgG from the mother to the child through the placenta, (2) protection of IgG from degradation, thus prolonging its half-life in serum. It is thought that the receptor recycles IgG from the endosomes. (See Holliger et al., Nat Biotechnol., 15 (7): 632-6 (1997)). The methods for pharmacokinetic analysis and determination of the half-life of the ligand will be familiar to those skilled in the art. Details can be found in Kenneth, A et al., Chemical Stability of Pharmaceuticals A Handbook for Pharmacists, and in Peters et al., Pharmacokinetc analysis: A Practical Approach (1996). Reference is also made to "Pharmacokinetics", M Gibaldi & D Perron, published by Marcel Dekker, Second Review, extra edition (1982), which describes the pharmacokinetic parameters, such as the half-lives of t-alpha and t-beta, and the area under the curve (AUC) Nucleic Acid Molecules, Vectors, and Host Cells. The invention also provides isolated and / or recombinant nucleic acid molecules encoding the anti-I L-1 R 1 ligands and the dAb monomers described herein, including the specific double ligands (e.g., ligands that bind to IL-1R1 and with serum albumin, ligands that bind IL-1R1 and TNFR1), and multispecific ligands (for example, ligands that bind with IL-1R1, with serum albumin, and with TNFR1 The invention also provides isolated and / or recombinant nucleic acid molecules that encode a protease resistant dAb monomer (e.g., pepsin, trypsin, elastase, chymotrypsin, carboxy peptidase, cathepsin (eg, cathepsin G), and protemase 3), or a ligand comprising a protease resistant dAb monomer, as described herein. In certain embodiments, the nucleic acid isolated and / or recombinant comprises a nucleotide sequence encoding a domain antibody (dAb) that specifically binds to I L-1 R, which inhibits the binding of IL-1 (e.g., IL-1a and / or IL) -1ß) and of I L-1 ra with IL-1R1, and comprising an amino acid sequence that is at least about 80 percent, at least about 85 percent, at least about 90 percent, when less about 91 percent, at least about 92 percent, at least about 93 percent, at least about 94 percent, at least about 95 percent, at least about 96 percent, at least about 97 percent, at least about 98 percent, or at least about 99 percent homologous to the amino acid sequence or a dAb selected from the group consisting of DOM4-122-23 (SEQ ID NO: 1), DOM4-122-24 (SEQ ID NO: 2), DOM4-122 (SEQ ID NO: 95), DOM4-122-1 (SEQ ID NO: 96), DOM4- 122-2 (SEQ ID NO: 97), DOM4-122-3 (SEQ ID NO.98), DOM4-122-4 (SEQ ID NO: 99), DOM4-122-5 (SEQ ID NO: 100), DOM4-122-6 (SEQ ID NO: 101) ), DOM4-122-7 (SEQ ID NO: 102), DOM4-122-8 (SEQ ID NO: 103), DOM4-122-9 (SEQ ID NO: 104), DOM4-122-10 (SEQ ID NO. : 105), DOM4-122-11 (SEQ ID NO: 106), DOM4-122-12 (SEQ ID NO: 107), DOM4-122-13 (SEQ ID NO: 108), DOM4-122-14 (SEQ ID NO: 109), DOM4-122-15 (SEQ ID NO: 110), DOM4-122-16 ( SEQ ID NO: 111), DOM4-122-17 (SEQ ID NO: 112), DOM4-122-18 (SEQ ID NO.113), DOM4-122-19 (SEQ ID NO: 114), DOM4-122- 20 (SEQ ID NO -115), DOM4-122-21 (SEQ ID NO: 116), DOM4-122-22 (SEQ ID NO: 117), DOM4-122-25 (SEQ ID NO: 118), DOM4-122-26 (SEQ ID NO: 119), DOM4-122-27 (SEQ ID NO: 120), DOM4-122-28 ( SEQ ID NO: 121), DOM4-122-29 (SEQ ID NO: 122), DOM4-122-30 (SEQ ID NO.123), DOM4-122-31 (SEQ ID NO: 124), DOM4-122- 32 (SEQ ID NO: 125), DOM4-122-33 (SEQ ID NO: 126), DOM4-122-34 (SEQ ID O 127), DOM4-122-35 (SEQ ID NO.128 DOM4-122-36 (SEQ ID 129), DOM4-122-37 (SEQ ID NO: 130 DOM4- 122-38 (SEQ ID O 131), DOM4- 122-39 (SEQ ID NO: 132 DOM4- 122-40 (SEQ ID O 133), DOM4- 122-41 (SEQ ID NO.134 DOM4- 122-42 (SEQ ID NO 135), DOM4- 122-43 (SEQ ID NO: 136 DOM4- 122-44 (SEQ ID NO 137), DOM4- 122 45 (SEQ ID NO: 138 DOM4- 122-46 (SEQ ID NO 139), DOM4- 122 • 47 (SEQ ID NO: 140 DOM4- 122-48 (SEQ ID NO 141), DOM4- 122 • 49 (SEQ ID NO: 142 DOM4- 122-50 (SEQ ID NO 143), DOM4- 122 -51 (SEQ ID NO: 144 DOM4- 122-52 (SEQ ID NO 145), DOM4- 122 -54 (SEQ ID NO: 146 DOM4- 122-55 SEQ ID NO 147), DOM4- 122 -56 (SEQ ID NO: 148 DOM4- 122-57 SEQ ID NO 149), DOM4- 122 -58 (SEQ ID NO: 150 DOM4- 122-59 SEQ ID NO 151), DOM4 122 -60 (SEQ ID NO: 152 DOM4- 122-61 SEQ ID NO 153), DOM4 -122 -62 (SEQ ID NO: 154 DOM4 122-63 SEQ ID NO 155), DOM4 -122 -64 (SEQ ID NO: 156 DOM4 • 122-65 SEQ ID NO 157), DOM4 -122-66 (SEQ ID NO.158 DOM4 -122-67 [SEQ ID NO 159), DOM4 -122 -68 (SEQ ID NO: 160 DOM4 -122-69 [SEQ ID NO 161), DOM4 -122 -70 (SEQ ID NO: 162 DOM4 -122-71 (SEQ ID NO 163), DOM4-122-72 (SEQ ID NO: 164), and DOM4-122-73 (SEQ ID NO 165). In certain embodiments, the isolated and / or recombinant nucleic acid comprises a nucleotide sequence that encodes a domain antibody monomer (dAb) that specifically binds to IL-1R1, and that inhibits the binding of IL-1 to the receptor, where this nucleotide sequence has when less about 80 percent, at least about 85 percent, at least about 90 percent, at least about 91 percent, at least about 92 percent, at least about 93 percent, at least about 94 percent, at least about 95 percent, at least about 96 percent, at least about 97 percent, at least about 98 percent, or at least about 99 percent sequence identity nucleotides with a nucleotide sequence selected from the group consisting of DOM4-122-23 (SEQ ID NO: 1), DOM4-122-24 (SEQ ID NO: 2), DOM4-122 (SEQ ID NO: 95) , DOM4-122-1 (SEQ ID NO: 96), DOM4-122-2 (SEQ ID NO: 97), DOM4-122-3 (SEQ ID NO: 98), DOM4-122-4 (SEQ ID NO: 99), DOM4-122-5 (SEQ ID NO: 100), DOM4-122-6 (SEQ ID NO: 101), DOM4-122-7 (SEQ ID NO: 102), DOM4-122-8 (SEQ ID NO: 103), DOM4-122-9 (SEQ ID NO: 104), DOM4-122-10 (SEQ ID NO: 105) ), DOM4-122-11 (SEQ ID NO: 106), DOM4-122-12 (SEQ ID NO: 107), DOM4-122-13 (SEQ ID NO: 108), DOM4-122-14 (SEQ ID NO. : 109), DOM4-122-15 (SEQ ID NO: 110), DOM4-122-16 (SEQ ID NO: 111), DOM4-122-17 (SEQ ID NO: 112), DOM4-122-18 (SEQ ID NO: 113), DOM4-122-19 (SEQ ID NO: 114), DOM4-122-20 (SEQ ID NO: 115) ), DOM4-122-21 (SEQ ID NO: 116), DOM4-122-22 (SEQ ID NO: 117), DOM4-122-25 (SEQ ID NO: 118), DOM4-122-26 (SEQ ID NO. : 119), DOM4-122-27 (SEQ ID NO: 120), DOM4-122-28 (SEQ ID NO: 121), DOM4-122-29 (SEQ ID NO: 122 DOM4-122-30 (SEQ ID NO: 123) DOM4- 122-31 (SEQ ID NO: 124 DOM4- 122-32 (SEQ ID NO: 125) DOM4-122-33 (SEQ ID NO: 126 DOM4-122-34 (SEQ ID NO: 127) DOM4- 122-35 (SEQ ID NO: 128 DOM4- 122-36 (SEQ ID NO: 129) DOM4- 122-37 (SEQ ID NO: 130 DOM4- 122-38 (SEQ ID NO: 131) DOM4- 122-39 (SEQ ID NO: 132 DOM4- 122-40 (SEQ ID NO: 133) DOM4- 122-41 (SEQ ID NO: 134 DOM4- 122-42 (SEQ ID NO: 135) DOM4- 122-43 (SEQ ID NO: 136 DOM4- 122-44 (SEQ ID NO: 137) DOM4- 122-45 (SEQ ID NO: 138 DOM4- 122-46 (SEQ ID NO: 139) DOM4- 122-47 (SEQ ID NO: 140 DOM4- 122-48 (SEQ ID NO: 141) DOM4- 122-49 (SEQ ID NO: 142 DOM4- 122-50 (SEQ ID NO: 143) DOM4- 122-51 (SEQ ID NO: 144 DOM4- 122-52 (SEQ ID NO: 145) DOM4-122-54 (SEQ ID NO: 146 DOM4- 122-55 (SEQ ID NO: 147) DOM4- 122-56 (SEQ ID NO: 148 DOM4- 122-57 (SEQ ID NO: 149) DOM4 • 122-58 (SEQ ID NO: 150 DOM4- 122-59 (SEQ ID NO: 151) DOM4 • 122-60 (SEQ ID NO: 152 DOM4- 122-61 (SEQ ID NO: 153) DOM4 -122-62 (SEQ ID NO: 154 DOM4- 122-63 (SEQ ID NO: 155) DOM4 -122-64 (SEQ ID NO: 156 DOM4 -122-65 (SEQ ID NO: 157) DOM4 -122-66 (SEQ ID NO: 158 DOM4 -122-67 (SEQ ID NO: 159) DOM4 -122-68 (SEQ ID NO: 160 DOM4 -122-69 (SEQ ID NO: 161) DOM4 -122-70 (SEQ ID NO: 162 DOM4 -122-71 (SEQ ID NO: 163) DOM4-122-72 (SEQ ID NO: 164), and DOM4-122-73 (SEQ ID NO: 165). In other embodiments, the isolated and / or recombinant nucleic acid comprises a nucleotide sequence encoding a protease resistant dAb (e.g., pepsin, trypsin, elastase, chymotrypsin, carboxy peptidase, cathepsin (eg, cathepsin G), and protemase 3), as described herein The invention also provides a vector comprising a recombinant nucleic acid molecule of the invention In certain embodiments, the vector is an expression vector comprising one or more expression control elements, or sequences that are operably linked to the recombinant nucleic acid of the invention. The invention also provides a recombinant host cell comprising a recombinant nucleic acid molecule or a vector of the invention Vectors (eg, plasmids, phagemids), expression control elements, host cells, and methods suitable for producing host cells recombinants of the invention, are well known in the art, and the examples are further described herein. Suitable expression vectors may contain a number of components, for example, a replication origin, a selectable marker gene, one or more elements of expression control, such as a transcription control element (e.g., promoter, enhancer, terminator), and / or one or more translation signals, a signal sequence, or a leader sequence, and the like Control elements of expression and a signal sequence, if present, may be provided by the vector or another source. For example, the transcriptional and / or translational control sequences of a cloned nucleic acid encoding an antibody chain can be used to direct the expression A promoter can be provided for expression in a desired host cell. The promoters may be constitutive or inducible. For example, a promoter may be operably linked to a nucleic acid encoding an antibody, an antibody chain, or a portion thereof, such as to direct transcription of the nucleic acid. A variety of suitable promoters are available for prokaryotic hosts (e.g., lac, tac, T3, T7 promoters for E. coll), and eukaryotes (e.g., early or late promoter from simian virus 40, long terminal repeat promoter of Rous sarcoma virusIn addition, the expression vectors typically comprise a selectable marker for the selection of the host cells bearing the vector, and in the case of a replicable expression vector, a replication origin. genes encoding products that confer resistance to antibiotics or drugs are common selectable markers, and can be used in prokaryotic cells (eg, lactamase gene (ampicillin resistance), Tet gene for tetracycline resistance), and eukaryotic cells (e.g., genes for resistance to neomycin (G418 or geneticin), gpt (mycophenolic acid), ampicillin, or hygromycin). The dihydrofolate reductase marker genes allow selection with methotrexate in a variety of hosts. Genes that encode the genetic product of auxotrophic markers of the host (for example, LEU2, URA3, HIS3), are frequently used as selectable markers in yeast. The use of viral (e.g., baculovirus) or phage vectors, and vectors that are capable of integrating into the genome of the host cell, such as retroviral vectors, is also contemplated. Expression vectors suitable for expression in mammalian cells and in prokaryotic cells (E. coli), insect cells (Schnieder S2 cells from Drosophila, Sf9), and in yeast (P. methanolica, P. pastoris, S. cerevisiae ), are well known in this field. Suitable host cells can be prokaryotic, including bacterial cells, such as E. coli, B. subtilis, and / or other suitable bacteria; eukaryotic cells, such as fungal or yeast cells (e.g., Pichia pastoris, Aspergillus sp., Saccharomyces cerevisiae, Schizosaccharomyces pombe, Neurospora crassa), and other lower eukaryotic cells, and higher eukaryotic cells, such as those of insects (e.g., Schnieder S2 cells from Drosophila, S9 insect cells (International Publication Number WO 94/26087 (O'Connor)), of mammals (eg, COS cells, such as COS-1 (ATCC, Accession number CRL-1650), and COS-7 (ATCC, Accession number CRL-1651), CHO (eg, ATTC, Accession number CRL-9096, CHO DG44 (Urlaub G. and Chasin, LA, Proc. Nati. Acad. Sci. USA, 77 (7): 4216-4220 (1980))), 293 (ATCC, Accession No. CRL-1573 ), HeLa (ATCC, Accession Number CCL-2), CV1 (ATCC, Number Access CCL-70), WOP (Dailey, L., et al., J Virol., 54: 739-749 (1985), 3T3, 293T (Pear W. S, et al., Proc. Nati, Acad. Sci. USA, 908392-8396 (1993)), NSO cells, SP2 / 0, HuT 78 cells, and the like, or plants (for example, tobacco) (See, for example, Ausubel, FM et al., Editors, Current Protocols m Molecular Biology, Greene Publishing Associates and John Wiley &Sons Ine (1993).) In some embodiments, the host cell is an isolated host cell and is not part of a multicellular organism (e.g., plant or animal) In preferred embodiments, the host cell is a non-human host cell. The invention also provides a method for the production of a ligand (eg, a dAb monomer, a specific double ligand, a multispecific ligand) of the invention, which comprises maintaining a recombinant host cell comprising a recombinant nucleic acid of the invention, under the ions suitable for the expression of the recombinant nucleic acid, whereby, the recombinant nucleic acid is expressed, and a ligand is produced. In some embodiments, the method further comprises isolating the ligand preparation of immunoglobulin-based ligands. Ligands (for example, specific double ligands, dAb monomers) according to the invention, can be prepared according to previously established techniques, used in the field of antibody engineering, for the preparation of scFv, "phage" antibodies, and other engineered antibody molecules Techniques for the preparation of antibodies, for example, are described in the following reviews and references cited therein Winter and Milstem, (1991) Nature 349293-299 , Pluckthun (1992) Immunological Reviews 130151-188, Wright et al., (1992) Cnt Rev Immunol 12 125-168, Holhger, P and Winter, G (1993) Curr Op Biotechn 4, 446-449, Carter, et al. (1995) J Hematother 4, 463-470, Chester , KA and Hawkms, RE (1995) Trends Biotechn 13, 294-300, Hoogenboom, HR (1997) Nature Biotechnol 15, 125-126, Fearon, D (1997) Nature Biotechnol 15, 618-619, Pluckthun, A and Pack, P (1997) Immunotechnology 3, 83-105, Carter, P and Merchant, AM (1997) Curr Opm Biotechnol 8, 449-454, Holliger, P and Winter, G (1997) Cancer Immunol Immunother 45,128-130 The appropriate techniques employed for the selection of variable domains of antibodies with a desired specificity, use libraries and selection procedures that are known in this field Natural libraries (Marks et al. (1991) J Mol Biol, 222581, Vaughan et al. (1996) Nature Biotech, 14309), which use reconfigured V genes harvested from cells- Human B, are well known to those skilled in the art Synthetic libraries (Hoogenboom and Winter (1992) J Mol Biol, 227381, Barbas et al. (1992) Proc Nati, Acad Sci USA, 894457, Nissim et al. (1994) EMBO J, 13692, Gpffiths et al. (1994) EMBO J, 133245, De Kruif et al. (1995) J. Mol Biol, 24897), are prepared by cloning immunoglobulin V genes, usually using polymerase chain reaction. Errors in the polymerase chain reaction process can lead to a high degree of random selection. The VH and / or V libraries can be screened against the target antigens or epitopes separately, in which case, the single-domain link is directly selected, or together. Library Vectors Systems A variety of selection systems are known in the art, which are suitable for use in the present invention. Examples of these systems are described below. Bactephophage-lambda expression systems can be screened directly as bacteriophage plaques or as colonies of sógenos, as previously described (Huse et al. (1989, Science, 246: 1275; and Koprowski (1990) Proc Nati Acad Sci USA, 87; Mullmax et al. (1990) Proc. Nati. Acad. Sci USA, 87: 8095; Persson et al. (1991) Proc. Nati Acad Sci USA, 88: 2432), as they are for use in the invention, although these expression systems can be used to track up to 106 different members of a library, they are not really suitable for tracking larger numbers (more than 106 members). library construction selection screening systems, which make it possible for a nucleic acid to be linked to the polypeptide that express As used herein, a selection display system is a system that allows the selection, by suitable means of display, of the individual members of the library, by linking the generic and / or target ligands. Selection for the isolation of desired members of large libraries are known in this field, as typified by phage display techniques. These systems, where various sequences of peptides are displayed on the surface of the filamentous bacteriophage (Scott and Smith (1990) Science, 249: 386), have proven useful for the creation of libraries of antibody fragments (and nucleotide sequences). encoding them), for the in vitro selection and amplification of specific antibody fragments that bind to a target antigen (MeCafferty et al., International Publication Number WO 92/01047) The nucleotide sequences encoding the variable regions are linked to the genetic fragments that encode the leader signals that direct them towards the pepplasmic space of E. coli, and as a result, the resulting antibody fragments are displayed on the surface of the bacteriophage, typically as fusions with the bacteriophage coating proteins (e.g. , plll or pVIII) In an alternative way, the antibody fragments are displayed extern amente on capsids of lambda phages (phagobodies) One advantage of phage-based display systems is that, Due to their biological systems, selected members of the library can be amplified simply by growing the phage containing the selected member of the library, in bacterial cells. Additionally, because the nucleotide sequence encoding the peptide member of the This library is contained on a phage or phagemid vector, sequencing, expression, and subsequent genetic manipulation are relatively straightforward. Methods for the construction of bacteriophage antibody display libraries and lambda phage display libraries are well known in this field (MeCafferty et al. (1990) Nature, 348552, Kang et al. (1991) Proc Nati Acad Sci USA, 884363, Clackson et al. (1991) Nature, 352624, Lowman et al. (1991) Biochemistry, 30 10832, Burton et al. (1991) Proc Nati Acad Sci USA, 88, 10134, Hoogenboom et al. (1991) Nucleic Acids Res, 194133, Chang et al. (1991) J Immunol, 1473610, Breithng et al. (1991) Gene, 104 147, Marks et al. (1991) supra, Barbas et al. 1992) supra, Hawkms and Winter (1992) J Immunol, 22867, Marks et al., 1992, J Biol Chem, 267-16007, Lerner et al. (1992) Science, 258-1313, incorporated herein by reference) A particularly convenient approach has been the use of scFv phage libraries (Huston et al., 1988, Proc. Nati Acad. Sci USA, 85.5879-5883; Chaudhary et al. (1990) Proc. Nati Acad. Sci USA, 87: 1066-1070; MeCafferty et al. (1990) supra; Clackson et al. (1991) Nature, 352624, Marks et al. (1991) J Mol. Biol, 222,581; Chiswell et al. (1992) Trends Biotech, 10.80, Marks et al. (1992) J. Biol. Chem., 267). Different modalities of scFv libraries displayed on bacteriophage coating proteins have been described. Refinements of the phage display approaches are also known, for example, as described in International Publications Nos. WO96 / 06213 and WO92 / 01047 (Medical Research Council and collaborators), and WO97 / 08320 (Morphosys), which are incorporated herein by reference. to the present as a reference. Other systems for generating polypeptide libraries involve the use of cell-free enzymatic machine for the m vitro synthesis of the members of the library. In one method, RNA molecules are selected by alternate rounds of selection against a target ligand, and amplification with pohmerase chain reaction (Tuerk and Gold (1990) Science, 249: 505, Ellmgton and Szostak (1990) Nature, 346,818 ) A similar technique can be used to identify DNA sequences that bind to a previously determined human transcription factor (Thiesen and Bach (1990) Nucleic Acids Res., 183203; Beaudry and Joyce (1992) Science, 257,635, International Publications Numbers WO 92/05258 and W092 / 14843) Of a In a similar manner, translational polyculture can be used to synthesize pohpeptides as a method for generating large libraries. These methods, which generally comprise stabilized pohysome complexes, are further described in International Publications Nos. WO88 / 08453, WO90 / 05785, WO90 / 07003 , WO91 / 02076, WO91 / 05058, and WO92 / 02536 Alternative display systems that are not phage-based, such as those disclosed in International Publication Numbers W095 / 22625 and W095 / 11922 (Affymax), utilize the polysomes to display polypeptides for selection A still further category of techniques involves the selection of repertoires in artificial compartments, which allow the linking of a gene with its genetic product. For example, a selection system is described where nucleic acids can be selected which encode desirable gene products in microcapsules formed by water-in-oil emulsions, in International Publications Nos. WO99 / 02671, WO00 / 40712, and in Tawfik and Gpffiths (1998) Nature Biotechnol 16 (7), 652-6. Genetic elements that encode a genetic product that has a desired activity are compartmentalized into microcapsules, and then transcribed and / or translated to produce their respective gene products (RNA or protein) within the microcapsules. Subsequently, the genetic elements that are classified are classified. produce the genetic product that has the desired activity This approach selects the genetic products of interest by detecting the desired activity by a variety of means. Library Construction The libraries intended for selection can be built using techniques known in this field, for example, as stipulated above, or can be purchased from commercial sources. Libraries that are useful in the present invention are described, for example, in International Publication Number WO99 / 20749. Once a vector system is selected, and one or more nucleic acid sequences encoding the polypeptides of interest are cloned into the library vector, diversity can be generated within the cloned molecules by undertaking mutagenesis prior to expression. , in an alternative way, the encoded proteins can be expressed and selected, as described above, before mutagenesis, and additional rounds of selection are carried out. The mutagenesis of nucleic acid sequences encoding structurally optimized peptides is carried out by conventional molecular methods. The polymerase chain reaction is particularly useful, or PCR (Mullis and Faloona (1987) Methods Enzymol, 155-335, incorporated herein by reference). The polymerase chain reaction, which uses multiple cycles of DNA replication catalyzed by a DNA-dependent, thermostable DNA polymerase, to amplify the target sequence of interest, is well known in the art of building different Antibody libraries have been discussed in Winter et al. (1994) Ann Rev Immunology 12, 433-55, and references cited therein. The pore chain reaction is carried out using template DNA (at least 1 fg, more usefully 1 to 1,000 ng), and at least 25 picomoles of oligonucleotide primers, it may be convenient to use a greater amount of primer when the primer pool is heavily heterogeneous, because each sequence is represented only by one small fraction of the molecules in the pool, and the amounts become limiting in the subsequent amplification cycles. A typical reaction mixture includes 2 microliters of DNA, 25 picomoles of oligonucleotide primer, 2.5 microchres of 10X 1 PCR regulator ( Perkin-Elmer, Foster City, CA), 04 microtiter dNTP 1 25 μM, 015 microliter (or 25 units) of Taq DNA pohmerase (Perkin-Elmer, Foster City, CA), and deionized water to a total volume of 25 microliters Mineral oil is superimposed, and the chain reaction of the pore is carried out using a programmable thermal cycler The duration and temperature of each step of a chain reaction cycle of the pohmerase, as well as the number of cycles, are adjusted according to the requirements of restpngency in force The tempering temperature and time are both determined by the efficiency with which it is expected that a primer is quenched to a template, and the degree of mismatching that is go to tolerate, obviously, when you simultaneously amplify and mutate nucleic acid molecules, mismatching is required, at least in the first round of synthesis. The ability to optimize the restpngency of the priming conditions of primers is well within the knowledge of a moderate expert in this field. a tempering temperature of between 30 ° C and 72 ° C The initial denaturation of the template molecules normally occurs between 92 ° C and 99 ° C for 4 minutes, followed by 20 to 40 cycles consisting of denaturation (94 ° C) at 99 ° C for 15 seconds to 1 minute), tempered (the temperature is determined as discussed above, from 1 to 2 minutes), and extended (72 ° C for 1 to 5 minutes, depending on the length of the amplified product) The final extension is usually for 4 minutes at 72 ° C, and can be followed by an indefinite step (from 0 to 24 hours) at 4 ° C Combination of Unique Variable Domains The variable domains of immunoglobulms useful in the invention, once selected, can be combined by a variety of methods known in the art, including covalent and non-covalent methods. Preferred methods include the use of po-peptide linkers, as described, for example, in with scFv molecules (Bird et al. (1988) Science 242423-426) Discussion of suitable linkers is provided in Bird et al., Science 242, 423-426, Hudson et al., Journal Immunol Methods 231 (1999) 177- 189, Hudson et al., Proc Nat Acad Sci USA 85, 5879-5883 The linkers are preferably flexible, allowing the two unique domains to interact An example of a linker is a linker (Gly4Ser) n, where n = 1 8, for example 1, 2, 3, 4,5, 6, 7, or 8 The linkers used in diabodies, which are less flexible, can also be used (Holhger et al. (1993) Proc Nat Acad Sci (USA) 906444-6448) In one embodiment, the linker employed is not an immunoglobulin link region. Variable domains can be combined using different linker methods. For example, the use of disulfide bridges, provided through naturally occurring or designed cistern residues to stabilize the VH-VH, V-VL, or VH-VL dimers (Reiter et al. (1994) Protein Eng 7697-704) or by remodeling the interface between the domains variables to improve the "adjustment", and therefore, the stability of the interaction (Ridgeway et al. (1996) Protein Eng 7617-621, Zhu et al. (1997) Protein Science 6781-788). Other techniques can be used to bind or stabilize the variable immunoglobulm domains. , and in particular the VH domains of antibodies, as appropriate. Characterization of Ligands The binding of a ligand (for example, monomer of dAb, double specific ligand) with its specific antigens or epitopes, it can be tested by methods that are familiar to those skilled in the art, and include ELISA. In a preferred embodiment of the invention, the binding is tested using the monoclonal phage ELISA. The phage ELISA can be carried out according to any procedure In this case, an exemplary protocol is stipulated immediately. Phage populations produced in each selection round can be traced to determine the binding by ELISA with the selected antigen or epitope, in order to identify "polyclonal" phage antibodies. The phage from the individual infected bacterial colonies can then be screened from these populations by ELISA to identify "monoclonal" phage antibodies. It is also desirable to screen the fragments of soluble antibodies for binding to the antigen or epitope, and this it can also be undertaken by ELISA, using reagents, for example, against a C- or N-terminal mark (see, for example, Winter et al., (1994) Ann. Rev Immunology 12, 433-55, and references cited in the same) The diversity of selected phage monoclonal antibodies can also be assessed by gel electrophoresis of the polymerase chain reaction products (Marks et al., 1991, supra, Nissim et al., 1994, supra), poll (Tomhnson et al. (1992) J Mol Biol 227, 776), or by sequencing the vector DNA Structure of Ligands In the case of selecting the immunoglobulin variable domains from the V-gene repertoires, for example, using the phage display technology as described herein, then these variable domains comprise a region of universal structure, such that they can be recognized by a specific generic ligand, as defined herein. The use of universal structures, generic labels, and the like, is described in International Publication No. WO99 / 20749. V-gene repertoires, the variation in the sequence of the polypeptide is preferably located within the structural cycles of the variable domains. The polypeptide sequences of any variable domain can be altered by mixing the DNA or by mutation, in order to improve the interaction of each variable domain with its complementary pair The DNA mixture is known in the a, and is taught, for example, by Stemmer, 1994, Nature 370389-391, and in U.S. Patent Number 6,297,053, both of which are incorporated herein by reference. Other methods of mutagenesis are well known. by experts in this field In general, nucleic acid molecules and vector constructs required for the selection, preparation, and formatting of ligands can be constructed and manipulated, as stipulated in conventional laboratory manuals, such as Sambrook and collaborators (1989) Molecular Cloning A Laboratory Manual, Cold Spring Harbor, USA Manipulation of nucleic acids useful in the present invention is typically carried out in recombinant vectors. As used herein, "vector" refers to a separate element that is used to introduce heterologous DNA into the cells for expression and / or replication thereof The methods by which they are selected and constructed, and subsequently these vectors are used, are well known to one of ordinary skill in the art. Numerous vectors are publicly available. available, including bacterial plasmids, bacteriophages, artificial chromosomes, and episomal vectors. These vectors can be used for simple cloning and mutagenesis, alternatively, the gene expression vector is employed. A useful vector according to the invention can be selected to accommodate a polypeptide coding sequence of one size wanted, typically from 025 kilobases (kb) to 40 kilobases or more in length A suitable host cell is transformed with the vector after the in vitro cloning manipulations Each vector contains different functional components, which generally include a cloning site (or polylinker "), a replication origin and at least one selectable marker gene. If a given vector is an expression vector, it additionally possesses one or more of the following an enhancer, promoter, transcription termination, and signal sequences, each a placed in the vicinity of the cloning site, such that they are operably linked to the gene encoding a ligand according to the invention. Both the cloning and expression vectors generally contain nucleic acid sequences which make it possible for the vector to replicate in one or more selected host cells. Typically, in cloning vectors, this sequence is one that makes it possible for the vector to replicate independently of the chromosomal DNA of the host, and includes replication origins or sequences that replicate autonomously. These sequences are well known for a variety of bacteria, yeast, and viruses. The replication origin of the plasmid pBR322 is suitable for most of the gram-negative bacteria, the origin of the plasmid of 2 micras is suitable for the yeast, and different viral origins (for example, SV 40, adenovirus) are useful for the vectors of cloning in mammalian cells. Generally speaking, replication origin is not needed for mammalian expression vectors, unless they are used in mammalian cells capable of replicating high levels of DNA, such as COS cells. Conveniently, a cloning or expression vector may contain a selection gene, also referred to as a selectable marker. This gene encodes a protein necessary for the survival or growth of transformed host cells cultured in a selective culture medium.
Accordingly, host cells not transformed with the vector containing the selection gene will not survive in the culture medium. Typical selection genes encode proteins that confer resistance to antibiotics and other toxins, eg, ampicillin, neomycin, methotrexate, or tetracycline, auxotrophic complement deficiencies, or provide critical nutrients not available in the culture medium. Because the replication of the vectors encoding a ligand according to the present invention is most conveniently carried out in E. coli, a selectable marker of E. coli, for example, the β-gene, is useful. lactamase that confers resistance to the antibiotic ampicillin. These can be obtained from E. coli plasmids, such as pBR322, or a pUC plasmid, such as pUC18 or pUC19. Expression vectors usually contain a promoter that is recognized by the host organism, and is operably linked to the coding sequence of interest. This promoter can be inducible or constitutive. The term "operatively linked" refers to a juxtaposition wherein the described components are in a relationship that allows them to function in their intended manner. A control sequence "operably linked" with a coding sequence is ligated such that expression of the coding sequence is achieved under conditions compatible with the control sequences.
Promoters suitable for use with prokaryotic hosts include, for example, the β-lactamase and lactose promoter systems, alkaline phosphatase, the tptophan (trp) promoter system, and hybrid promoters, such as the tac promoter. Promoters to be used in bacterial systems will also generally contain a Shine-Delgarno sequence operably linked to the coding sequence. Preferred vectors are the expression vectors that make possible the expression of a nucleotide sequence corresponding to a member of the pohpeptide library. , the selection with the first and / or the second antigen or epitope, can be carried out by a separate propagation and expression of a single clone expressing the member of the polypeptide library, or by using any display system of selection. As described above, the preferred screening display system is the display of bacteriophages., phage or phagemid vectors can be used, for example, plT1 or plT2. The leader sequences useful in the invention include pelB, stll, ompA, phoA, bla, and pelA. An example is the phagemid vectors that have a replication origin of E. coli (paca the double-stranded replica), and also a replication origin of the phage (for the production of the single-stranded DNA). The manipulation and expression of these vectors are well known in the art (Hoogenboom and Winter (1992) supra, Nissim et al. (1994) supra) Said in a short way, the vector contains a β-lactamase gene to confer selectivity to the phagemid, and a lac promoter upstream of an expression cassette consisting (N- to C-terminal) in a pelB leader sequence (which directs the expressed polypeptide to the pepplasmic space ), a multiple cloning site (for the cloning of the nucleotide version of the library member), optionally one or more peptide tags (for detection), optionally one or more TAG stop codons, and the phage protein plll Therefore, using different suppressor and non-suppressor strains of E coli, and with the addition of glucose, isopropyl thio-β-D-galactoside (IPTG), or an auxiliary phage, such as VCS M13, the vector can be replicated as a plasmid without expression, it can produce large amounts of the member of the polypeptide library alone, or it can produce phages, some of which contain at least one copy of the fusion of the polypeptide-11 its surface The construction of vectors encoding ligands according to the invention employs conventional ligation techniques. Isolated vectors or DNA fragments are dissociated, tailored, and religated in the desired form to generate the vector required If desired, an analysis can be carried out to confirm that the correct sequences are present in the constructed vector, in a known manner The suitable methods to construct expression vectors, for the preparation of m vitro transcripts, paca the production of DNA in the host cells, and to carry out the analyzes in order to evaluate expression and function, are known to those skilled in the art. The presence of a genetic sequence in a sample is detected, or its amplification and / or expression is quantified, by conventional methods, such as Southern or Northern analysis, Western blot, staining of DNA, RNA or protein spots, in situ hybridization, Immunocytochemistry, or Sequence Analysis of Nucleic Acid or Protein Molecules Those skilled in the art will readily envision how these methods can be modified, if desired. Skeletons Skeletons can be based on immunoglobulin molecules, or can be of a non-immunoglobulin origin, as stipulated above. Preferred immunoglobulin skeletons, as defined herein, include any one or more of those selected from the following: an immunoglobulm molecule comprising at least: (i) the CL domain (kappa or lambda subclass) of an antibody; or (n) the CH1 domain of an antibody heavy chain; an immunoglobuhne molecule comprising the CH1 and CH2 domains of an antibody heavy chain; an immunoglobulin molecule comprising the CH1, CH2, and CH3 domains of an antibody heavy chain; or any of the subset (n) in conjunction with the CL domain (kappa or lambda subclass) of an antibody. articulation region These combinations of domains, for example, can mimic natural antibodies, such as IgG or IgM, or fragments thereof, such as Fv, scFv, Fab, or F (ab ') 2 molecules. The experts in this field you will be aware that this list does not intend to be exhaustive. Protein Scaffolds Each epitope binding domain comprises a protein scaffold and one or more complementarity determining regions that are involved in the domain-specific interaction with one or more epitopes. Conveniently, an epitope binding domain according to the present invention comprises three complementarity determining regions. Suitable protein scaffolds include any of those selected from the group consisting of the following: those based on immunoglobulin domains, those based on fibronectin, those based on affibodies, those based on CTLA4, those based on chaperones, such as GroEL, those based on little na, and those based on bacterial Fe receptors SpA and SpD Those skilled in the art will appreciate that this list is not intended to be exhaustive. Scaffolds for Use in the Construction of Ligands Selecting the Conformation of the Main Chain The members of the immunoglobulin super family share a similar fold for their polypeptide chain. For example, although antibodies are highly diverse in terms of its primary sequence, the comparison of the sequences and crystallographic structures has revealed that, contrary to the expectation, five of the six antigen binding cycles of the antibodies (H1, H2, L1, L2, L3) adopt a limited number of conformations of the main chain, or canonical structures (Chothia and Lesk (1987) J Mol. Biol, 196: 901; Chothia et al., (1989) Nature, 342,877). The analysis of the lengths of the cycles and the key residues has made it possible, therefore, to predict the conformations of the main chain of H1, H2, L1, L2, and L3 that are found in most human antibodies. (Chothia et al. (1992) J Mol Biol, 227-799, Tomlmson et al. (1995) EMBO J, 14: 4628; Williams et al. (1996) J. Mol Biol., 264,220). Although the H3 region is much more diverse in terms of sequence, length, and structure (due to the use of the D segments), it also forms a limited number of conformations of the main chain for short cycle lengths, which depend on the length and the presence of particular residues, or types of residues, in key positions in the cycle and in the structure of the antibody (Martin et al., (1996) J. Mol. Biol, 263. 800, Shirai et al., ( 1996) FEBS Letters, 399 1). Gando libraries and / or domains can be designed where certain cycle lengths and key residues have been chosen, to ensure that the conformation of the main chain of the members is known. In a convenient way, these are Real conformations of the immunoglobulin super-famiha molecules found in nature, to minimize the chances of them not being functional, as discussed in the previous section Germline V gene segments serve as an adequate basic structure To build libraries of antibodies or T-cell receptors, other sequences are also useful Variations may occur at a low frequency, such that a small number of functional members may possess an altered main chain conformation, which does not affects its function The theory of the canonical structure is also useful to evaluate the number of different conformations of the main chain encoded by the ligands, to predict the conformation of the main chain based on the sequences of the ligands, and to choose the residues for diversification that does not affect the canonical structure It is known that, in the domain V ?, Cycle L1 can adopt one of four canonical structures, cycle L2 has a single canonical structure, and that 90 percent of domains V? humans adopt one of four or five canonical structures for the L3 cycle (Tomlinson et al. (1995) supra), therefore, in the V domain? only, can different canonical structures be combined to create a range of different conformations of the main chain Since the domain V? codifies a different range of canonical structures for cycles L1, L2, and L3, and that domains V? and V? can be paired with In any VH domain that can code several canonical structures for cycles H1 and H2, the number of combinations of canonical structures observed for these five cycles is very large. This implies that the generation of diversity in the conformation of the main chain can be essential for the production of a wide range of binding specificities. However, by building an antibody library based on a single conformation of the known backbone, it has been found that, contrary to expectation, diversity in the shaping of the backbone is not required to generate sufficient diversity to address substantially all antigens. Still more surprisingly, the individual conformation of the main chain does not need to be a consensus structure - a single conformation that naturally occurs as the basis for the entire library can be used. Therefore, in a preferred aspect, the double specific ligands of the invention possess a single conformation of the known backbone. The only conformation of the main chain that is selected is preferably a common place among the molecules of the immunoglobulin super family type in question. A conformation is a common place when it is observed that a significant number of molecules that occur naturally adopt it. In accordance with the foregoing, in a preferred aspect of the invention, the natural presentation of the different conformations of the main chain for each binding cycle of an immunoglobulin domain is considered separately, and then a naturally occurring variable domain is selected, which possesses the desired combination of main chain conformations for the different cycles. If there is no none available, the closest equivalent can be chosen. It is preferable that the desired combination of main chain conformations for the different cycles be created by selecting the germ line genetic segments that encode the desired main chain conformations. It is more preferable that the selected germline genetic segments are frequently expressed in nature, and it is highly preferable that they are the most frequently expressed of all the natural germline genetic segments in the design of genes (for example, dAbs) or libraries thereof, the incidence of the different conformations of the main chain can be considered separately for each of the six antigen binding cycles For H1, H2, L1, L2, and L3, it selects a given conformation that is adopted between 20 percent and 100 percent of the antigen binding cycles of naturally occurring molecules. Typically, its observed incidence is greater than 35 percent (that is, between 35 percent and 100 percent), and ideally, greater than 50 percent, or even greater than 65 percent. Because the vast majority of H3 cycles do not have canonical structures, it is It is preferable to select a conformation of the main chain that is a common place among these cycles, which do exhibit canonical structures. For each of the cycles, therefore, the conformation most frequently observed in the natural repertoire is selected. In human antibodies, the most popular canonical structures (CS) for each cycle are as follows: Hl -CS 1 (79 percent of the expressed repertoire), H2-CS 3 (46 percent), L1 - CS 2 of VK ( 39 percent), L2 - CS 1 (100 percent), L3 - CS 1 of V? (36 percent) (the calculation assumes a ratio of?:? Of 70'30, Hood et al. (1967) Cold Spring Harbor Symp Quant. Biol, 48: 133). For H3 cycles that have canonical structures, a length of CDR3 (Kabat et al. (1991) Sequences of proteins of immunological interest, of seven residues with a salt bridge from the residue 94 to residue 101, seems to be the most common There are at least 16 sequences of human antibodies in the EMBL data library with the required length of H3 and key residues to form this conformation, and at least two crystallographic structures in the database of proteins that can be used as a basis for the modeling of antibodies (2cgr and 1 tet) The germline genetic segments most frequently expressed in this combination of canonical structures are segment VH 3-23 8DP-47), segment JH JH4b, segment V? 02/012 (DPK9), and segment J? J? 1. The segments VH DP45 and DP38 are also These segments, therefore, can be used in combination as a basis for building a library with the conformation of the desired individual main chain. In an alternative way, instead of deselecting the conformation of the individual main chain based on the natural presentation of the different conformations of the main chain for each of the link cycles in isolation, the natural presentation of the conformation combinations of the main chain as the basis for choosing the conformation of the individual main chain In the case of antibodies, for example, one can determine the natural presentation of combinations of canonical structures for any two, three, four, five, or all six cycles of antigen binding Here, it is preferable that the selected conformation is a common site in naturally occurring antibodies, and more preferably that it is more frequently observed in the natural repertoire. Thus, in human antibodies, for example, when considering natural combinations of The five antigen binding cycles, H1, H2, L1, L2, and L3, determine the most common combination of canonical structures, and then combine with the most popular conformation for the H3 cycle, as a basis for selecting the conformation of the individual main chain. Diversification of the Canonical Sequence Having selected several conformations of the chain In the known master cells, or preferably a single conformation of the known backbone, ligands (for example, dAbs) or libraries can be constructed for use in the invention, varying the binding site of the molecule, in order to generate a repertoire with structural and / or functional diversity This means that variants are generated, in such a way that they possess sufficient diversity in their structure and / or function, in such a way that they are capable of providing a range of activities. The desired diversity is typically generated by varying the selected molecule in one or more positions. The positions to be changed can be randomly selected, or selected in a preferable manner. Then the variation can be achieved either by random selection, during which the resident amino acid is replaced by any amino acid or analogue thereof, natural or synthetic, producing a very large number of variants, or by replacing the resident amino acid with one or more than a defined subset of amino acids, producing a more limited number of variants. Different methods have been reported to introduce this diversity. Poxmerase chain reaction susceptible to error can be used (Hawkins et al. (1992) J. Mol. Biol, 226889), chemical mutagenesis (Deng et al., (1994) J. Biol. Chem., 2699533), or strains bacterial mutants (Low et al. (1996) J. Mol. Biol., 260: 359), to introduce random mutations in the genes that encode the molecule Methods for mutating the selected positions are also well known in the art, and include the use of mismatched oligonucleotides or degenerate oligonucleotides, with or without the use of the polymerase chain reaction. For example, several libraries of synthetic antibodies have been created by directing the mutations toward the antigen binding cycles. The H3 region of a human tetanus toxoid binding Fab has been randomly selected to create a range of novel binding specificities (Barbas et al. (1992) Proc. Nati. Acad. Sci. USA, 89: 4457). The random or semi-random H3 and L3 regions have been appended to the germline V gene segments to produce large libraries with unmutated structure regions (Hoogenboom and Winter (1992) J. Mol. Biol, 227: 381; Barbas et al. (1992) Proc. Nati, Acad. Sci. USA, 89: 4457, Nissim et al. (1994) EMBO J, 13: 692; Griffiths et al. (1994) EMBO J, 13: 3245; De Kruif et al. (1995) J. Mol. Biol, 248: 97). This diversification has been extended to include some or all of the other antigen binding sites (Crameri et al. (1996) Nature Med., 2: 100; Riechmann et al. (1995) Bio / Technology, 13: 475; Morphosys, International Publication WO97 / 08320, supra). Because the random selection of cycles has the potential to create approximately more than 1015 structures for H3 only, and similarly a large number of variants for the other five cycles, it is not feasible, employing the technology of Current transformation, or even using systems without cells, produce a library that represents all possible combinations. For example, in one of the largest libraries built to date, 6x1010 different antibodies were generated, which is only a fraction of the potential diversity for a library of this design (Griffiths et al. (1994), supra). Preferably, only those residues that are directly involved in the creation or modification of the desired function of the molecule are diversified. For many molecules, the function will be linked to an objective, and therefore, diversity should be concentrated in the target binding site, while shifting residues that are crucial to the overall packaging of the molecule are avoided., or to maintain the conformation of the main chain selected. Diversification of the Canonical Sequence as it is applied to the Antibody Domains. In the case of antibody-based ligands (e.g., dAbs), the binding site for the target is most often the antigen binding site. Accordingly, preferably only the residues at the antigen binding site are varied. These residues are extremely diverse in the repertoire of human antibodies, and are known to make contacts in the high resolution antibody / antigen complexes. For example, in L2, it is known that positions 50 and 53 are diverse in the antibodies that occur naturally, and it is observed that they make contact with the antigen. In contrast, the conventional approach would have been to diversify all the residues in the corresponding complementarity determining region (CDR1), as defined by Kabat et al. (1991, supra), some seven residues, comparing with the two diversified in the library to be used according to the invention. This represents a significant improvement in terms of the functional diversity required to create a range of antigen binding specificities. In nature, the diversity of antibodies is the result of two processes: somatic recombination of the genetic segments of the germline V, D, and J, to create a pure primary repertoire (the so-called as germline and union diversity). ), and somatic hyper-mutation of the resulting reconfigured V genes. Analysis of human antibody sequences has shown that the diversity in the primary repertoire is focused on the center of the antigen binding site, while the somatic hyper-mutation extends the diversity to regions at the periphery of the antigen binding site , which are highly conserved in the primary repertoire (see Tomlinson et al., (1996) J. Mol. Biol., 256: 813). This complementarity has probably evolved as an efficient strategy to search for sequence space, and, although apparently unique to antibodies, it can be easily applied to other polypeptide repertoires. The waste that is vary they are a subset of those that form the link site for the goal. Different subsets (including overlaps) of waste at the target link site are diversified at different stages during the selection, if desired. In the case of an antibody repertoire, an initial "pure" repertoire can be created, where some, but not all, residues at the antigen binding site are diversified. As used herein in this context, the term "pure" refers to antibody molecules that do not have a previously determined purpose. These molecules resemble those that are encoded by the immunoglobulin genes of an individual who has not undergone immune diversification, as is the case with fetal and newborn individuals whose immune systems have not yet been assaulted by a wide variety of antigenic stimuli This repertoire is then selected against a range of antigens or epitopes. If required, additional diversity can then be introduced outside the diversified region in the initial repertoire. This mature repertoire can be selected for a modified function, specificity, or affinity. The pure repertoires of binding domains for the construction of ligands wherein some or all of the residues at the antigen binding site are varied are known in the art. (See International Publications Numbers WO 2004/058821, WO 2004/003019, and WO 03/002609). The "primary" library imitates the primary natural repertoire, with diversity restricted to residues in the center of the antigen binding site that are diverse in the V-gene segments of the germline (diversity of the germline), or diversify during the recombination process (binding diversity) diversify include, but are not limited to, H50, H52, H52a, H53, H55, H56, H58, H95, H96, H97, H98, L50, L53, L91, L92, L93, L94 and L96 in the "somatic" library ", diversity is restricted to residues that are diversified during the recombination process (union diversity), or that are highly somatically mutated. These diversifying residues include, but are not limited to: H31, H33, H35, H95, H96, H97, H98, L30, L31, L32, L34 and L96. All the wastes listed above are known to be suitable for diversification into these libraries make contacts in one or more antibody-antigen complexes. Because in both libraries not all residues of the antigen binding site are varied, additional diversity is incorporated during the selection by varying the remaining residues, if it is desired to do it in this way. It will be apparent to one skilled in the art that any subset of any of these residues (or additional residues comprising the antigen binding site) can be used for the initial and / or subsequent diversification of the antigen binding site. In the construction of the libraries for use in the invention, the diversification of the selected positions is typically achieved at the level of the nucleic acid, altering the coding sequence that specifies the pohpeptide sequence, so that a number of possible amino acids (20 or a subset thereof) can be incorporated in that position Using the lUPAC nomenclature, the most versatile codon is NNK, which encodes all amino acids, as well as the TAG stop codon The NNK codon is preferably used in order to introduce the required diversity. Other codons are also useful that achieve the same ends, including the NNN codon, which leads to the production of codons Additional stoppage TGA and TAA A characteristic of the side chain diversity in the antigen binding site of human antibodies is a pronounced tilt that favors certain amino acid residues If the amino acid composition of the 10 most diverse positions is added in each of the regions VH, V ?, and V ?, more than 76 percent of the side chain diversity comes from only seven different residues, these being sepna (24 percent), tyrosma (14 percent), asparagma (11 percent), glycine (9 percent), alanine (7 percent), aspartate (6 percent), and threonine (6 percent) This inclination towards hydrophobic residues and towards small residues that can provide flexibility of the main chain, reflects the evolution of surfaces that are predisposed to link with a wide range of antigens or epitopes, and can help to explain the required promiscuity of antibodies in the primary repertoire Because it is preferable to mimic this distribution of amino acids, the distribution of amino acids at the positions to be varied preferably mimics that seen at the antigen binding site of the antibodies This bias in amino acid substitution allows the selection of certain polypeptides (not only antibody polypeptides) against a range of target antigens, is easily applied to any repertoire of polypeptides. There are different methods for varying the inclination of the amino acid distribution at the position (including the use of tp mutagenesis). -nucleotides, see International Publication Number WO97 / 08320), of which the preferred method, due to the ease of synthesis, is the use of conventional degenerate codons By comparing the amino acid profile encoded by all degenerate codon combinations ( with individual, double, triple, and quadruple degeneration in equal proportions in each position) with the use of natural amino acids, it is possible to calculate the most representative codon The codons (AGT) (AGC) T, (AGT) (AGC) C, and (AGT) (AGC) (CT) - is say, DVT, DVC, and DVY, respectively, using the lUPAC nomenclature - are those that are closest to the desired amino acid profile encoding 22 percent septen and 11 percent tyrosine, asparagma, glycine, alanine, aspartate, threonine, and cysteine Accordingly, preferably, libraries are constructed using any of the DVT, DVC, or DVY codons in each of the positions diversified Compositions and Therapeutic and Diagnostic Uses. The invention provides compositions comprising a ligand of the invention (e.g., double specific ligand, multispecific ligand, dAb monomer), and a pharmaceutically acceptable carrier, diluent, or excipient, and therapeutic and diagnostic methods employing the ligands or COMPOSITIONS OF THE INVENTION Ligands (e.g., specific double ligands, multispecific ligands, dAb monomers (according to the method of the present invention, can be used in therapeutic and prophylactic applications in vivo, in in vivo diagnostic applications, and The therapeutic and prophylactic uses of the ligands (for example, multispecific ligands, double specific ligands, dAb monomers) of the invention, involve the administration of the ligands according to the invention to a recipient mammal, such as a human The specific double and multispecific proteins (for example, specific double body formats) bind to the multimépic gen with high avidity. Specific double or multispecific ligands can allow the cross-linking of two gens, for example, in the recruitment of cytotoxic T-cells to mediate the annihilation of tumor cell lines Substally pure ligands, for example dAb monomers, of at least one homogeneity are preferred 90 to 95 percent, to be administered to a mammal, and a homogeneity of 98 to 99 percent or more is more preferred for pharmaceutical uses, especially when the mammal is a human being. Once purified, partially or until homogeneous, as desired, the ligands can be used diagnostically or therapeutically (including extracorporeally), or to develop and carry out immunofluorescent staining and assay procedures and the like (Lefkovite and Pernis, (1979). 1981), Immunological Methods, Volumes I and II, Academic Press, NY) For example, the derivatives (e.g., dAb monomers) of the present invention will typically find use in the prevention, suppression, or treatment of inflammation or conditions. Inflammatory, including acute inflammatory diseases and / or chronic inflammatory diseases The gandos (for example, dAb monomers) of the present invention can also be administered to inhibit the biological processes that are induced by the IL-1 binding (eg, IL). -1a and / or IL-1ß) with the IL-1R1 In the present application, the term "prevention" involves the administration of the composition pro Tector before the induction of the disease "Suppression" refers to the administration of the composition after an inductive event, but before the clinical onset of the disease. "Treatment" involves the administration of the protective composition after the symptoms of the disease become manifest. The ligands of the invention, including the monomers of dAb, can be administered to prevent, suppress, or treat a chronic inflammatory disease, allergic hypersensitivity, cancer, bacterial or viral infection, autoimmune disorders (which include, but are not limited to, type I diabetes, asthma, multiple sclerosis, lupus systemic ephematosus, inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), myasthenia gravis, and Behcet's syndrome), sopasis, endometritis, and abdominal adhesions (eg, post-abdominal surgery) The gandos of the invention, including dAb monomers, they can be administered to prevent, suppress, or treat lung inflammation, chronic obstructive respiratory disease (e.g., chronic bronchitis, chronic obstructive bronchitis, emphysema), asthma (e.g., steroid-resistant asthma), pneumonia ( for example, bacterial pneumonia, such as staphylococcal pneumonia), hypersensitivity pneumonitis, pulmonary infiltration with eosmofi lia, environmental lung disease, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboemboha, pleural disorders, mediastinal disorders, diaphragm disorders, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma , sarcoma, graft rejection, graft-versus-host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergillomas, aspergillosis, chronic bronchitis, emphysema, eosmophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease (IPD), influenza, nontuberculous mycobacterium, pleural effusion, pneumoconiosis, pneumocytosis, pulmonary actinomycosis, pulmonary alveolar protemosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X (eosinophilic granuloma), pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, Wegener's granulomatosis, and non-microcellular lung carcinoma The ligands of the invention, including the dAb monomers, can be administered to prevent, suppress, or treat influenza, respiratory disease associated with RSV , and viral (respiratory) lung disease The ligands of the invention, including the dAb monomers, can be administered to prevent, suppress, or treat osteoartptis or inflammatory arthritis. "Inflammatory arthritis" refers to joint diseases wherein the system immune is causing or exacerbating inflammation ion in the joint, and includes rheumatoid arthritis, juvenile rheumatoid arthritis, and spondyloarthropathies, such as ankylosing spondylitis, reactive arthritis, Reiter syndrome, sophatic arthritis, sopatic spondylitis, enteropathic arthritis, enteropathic spondylitis, juvenile spondyloarthropathy, and undifferentiated spondyloarthropathy. Inflammatory arthritis characterized in general by infiltration of synovial tissue and / or synovial fluid by leukocytes. Ligands according to the invention (e.g.
Specific double ligands, multispecific ligands, dAb monomers, which bind to extracellular targets involved in endocytosis (eg, Clathrin), can be endocytosed, making access to intracellular targets possible. In addition, specific double or multispecific ligands provide a way by which a binding domain (eg, a dAb monomer) that is capable of binding to an intracellular target can be delivered to an intracellular environment. This strategy requires, for example, a specific double ligand with physical properties that make it possible to remain functional within the cell. Alternatively, if the intracellular compartment of final destination is being oxidized, a good fold ligand may not need to remain disulfide free. Conveniently, specific double or multispecific ligands can be used to target cytokine receptors and other molecules that cooperate synergistically in therapeutic situations in the body of an organism. The invention, for example, provides a method for synergizing the activity of two or more binding domains (e.g., dAbs) that bind to cytokine receptors or other molecules, which comprises administering a specific double or multispecific ligand capable of link to these two or more molecules (eg, cytokine receptors). In this aspect of the invention, the specific double or multispecific ligand may be any specific double or multispecific ligand, for example, this aspect of the invention relates to combinations of the VH domains and the VL domains, the VH domains only, and the VL domains only. Synergism, in a therapeutic context, can be achieved in a number of ways. For example, target combinations can be therapeutically active only if both targets are targeted by the ligand, while targeting alone is not therapeutically effective. In another embodiment, an objective can only provide some therapeutic effect, but together with a second objective, the combination provides a synergistic increase in the therapeutic effect (an effect rather than an additive). Animal model systems are available that can be used to track the effectiveness of the ligands of the invention in protecting against, or treating, the disease. Methods for testing systemic lupus erythematosus (SLE) in susceptible mice are known in the art Knight et al. (1978) J. Exp. Med., 147: 1653; Reinersten et al. (1978) New Eng. J. Med., 299: 515). Myasthenia gravis (MG) is tested in female SJL / J mice by inducing the disease with the soluble AchR protein from another species (Lindstrom et al., (1988) Adv. Immunol., 42: 233). Arthritis is induced in a race of susceptible mice by injection of type II collagen (Stuart et al. (1984) Ann. Rev. Immunol., 42: 233). A model has been described by which adjuvant arthritis is induced in susceptible rats by injection of mycobactepane heat shock protein (Van Eden et al. (1988) Nature, 331 171) Thyroiditis is induced in mice by administration of thyroglobulin as described (Marón et al., (1980) J Exp Med., 152- 1115) Insulin dependent diabetes mellitus (IDDM) occurs naturally or can be induced in certain mouse breeds, such as those described by Kanasawa et al. (1984) Diabetology, 27: 113 EAE in mouse and rat serves as a model for multiple sclerosis in humans In this model, demyelinating disease is induced by the administration of a myelin basic protein (see Paterson (1986) Textbook of Immunopathology, Mischer et al., editors, Grunt and Stratton, New York, pages 179-213, McFarlm et al. (1973) Science, 179: 478, and Satoh et al., (1987) J Immunol., 138 179) Other suitable models are described herein. In general terms, the ligands will be used in a purified form together with Pharmacologically Appropriate Vehicles Typically, these vehicles include aqueous, aqueous or alcoholic / aqueous solutions, emulsions, suspensions, including serum and / or regulated media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, and Ringer's. lactated Suitable physiologically acceptable adjuvants, if necessary to maintain a polypeptide complex in suspension, can be selected from thickeners, such as carboxymethyl cellulose, polyvinyl pyrrolidone, gelatin, and alginates. Intravenous vehicles include fluid and nutrient replenishers and electrolyte replenishers, such as those based on Ringer's dextrose. Preservatives and other additives may also be present. as anti-microbial, anti-oxidants, chelating agents, and inert gases The formulation will depend on the route of administration, and the variety of suitable formulations that can be used, including the extended-release formulations (See, for example, Mack ( 1982) Remmgton's Pharmaceutical Sciences, 16th Edition) Legands (eg, dAb monomers) may be administered and / or formulated together with one or more additional therapeutic agents or active agents When a ligand is administered with an additional therapeutic agent, the ligand can be administered before, in a simultaneous manner with, or after the administration of the additional agent In general terms, the ligand (e.g., the dAb monomer) and the additional agent are administered in a manner that provides an overlap of the therapeutic effect. Additional agents that may be administered or formulated with the ligand of the invention include, for example. , different immunotherapeutic drugs, such as ciclospopna, methotrexate, adpamycin, or cisplatmo, antibiotics, antifungals, anti-viral agents, and immunotoxins For example, when the antagonist is administered to prevent, suppress, or treat pulmonary inflammation or a respiratory disease, can be administered in conjunction with phosphodiesterase inhibitors (eg, phosphodiesterase 4 inhibitors), bronchodilators (eg, beta2 agonists, anticolmerics, theophylline), short-acting beta-agonists (eg, albuterol , salbutamol, bambuterol, fenoterol, isoetepna, isoproterenol, levalbuterol, metaproterenol, pirbuterol, terbuta na, and tadlato), long-acting beta-agonists (eg, formoterol and salmeterol), short-acting anticolmerics (eg, ipratropium bromide and oxitropium bromide), long-acting anticholinergics (eg, tiotropium), theophylline (eg, short-acting formulations, long-acting formulations), inhaled steroids (eg, beclometne, budesonide, flunisolide, fluticasone propionate, and tpamcinolone ), oral steroids (eg, methyl-predmsolone, prednisolone, prednisolone, and prednisone), short-acting beta-agonists with anticoagulant combined lmérgicos (for example, albuterol / salbutamol / ipratropio, and fenoterol / ipratropio), beta-agonists of long action with combined inhaled steroids (for example, salmeterol / fluticasona, and formoterol / budesonide), and mucolytic agents (for example, erdosteína, acetyl cysteine, bromhecism, carbocysteine, guiafenesm, and iodized glycerol When the antagonist is administered to prevent, suppress, or treat arthritis (e.g., inflammatory arthritis (e.g., rheumatoid arthritis)), it may be administered in conjunction with an anti-inflammatory agent. - Rheumatic disease modifier (for example, methotrexate, hydroxychloroquine, sulfasalazma, leflunomide, azathiopan, D-penicillam, gold (oral or intramuscular), minocycline, ciclospopna, staphylococcal protein A), non-steroidal anti-inflammatory agent (for example, selective non-steroidal anti-inflammatory agents of COX-2, such as rofecoxib), salicylates, glucocorticoids (e.g., prednisone), and analgesics. Pharmaceutical compositions can include "cocktails" of different cytotoxic agents or other agents in conjunction with the ligands of the present invention, or even combinations of ligands according to the present invention having different specificities, such as the selected ligands using different target antigens or epitopes, whether they are grouped or not before administration. The route of administration of the pharmaceutical compositions according to the invention can be any of those commonly known to ordinary experts in the field For therapy, including, without limitation, immunotherapy, the selected ligands of the invention can be administered to any patient according to conventional techniques. Administration can be by any appropriate mode, including parenterally (eg, intravenous, intramuscular, mtrapepton intra-articular, intrathecal), transdermally, by the pulmonary route, or also, appropriately, by direct infusion with a catheter. Dosage and frequency of administration will depend on the age, sex, and condition of the patient, the concurrent administration of other drugs, contraindications and other parameters that should be taken into account by the clinician. Administration may be local (eg, local delivery to the lung by pulmonary administration, for example intranasal administration) or systemic, as indicated. Ligands of this invention can be lyophilized for storage, and can be reconstituted in a suitable vehicle before use. This technique has been shown to be effective with conventional immunoglobulins, and lyophilization and reconstitution techniques known in the art can be used in this field. by those skilled in the art that lyophilization and reconstitution can lead to different degrees of loss of antibody activity (for example, with conventional immunoglobulins, IgM antibodies tend to have a greater loss of activity than IgG antibodies), and that you may have to adjust the levels of upward use to compensate The compositions containing the present antagonists (e.g., ligands) or a cocktail thereof, can be administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, a suitable amount to carry out when less a partial inhibition, suppression, modulation, annihilation, or some other measurable parameter, of a population of selected cells, is defined as a "therapeutically effective dose". For example, for the treatment of pulmonary inflammation and / or a respiratory disease, can administer a sputum inhibitory amount, an inhibitory amount of bronchial biopsy inflammation, an inhibitory amount of dyspnea, a forced expiration volume in a second increasing amount (FEV (1)), an amount increasing the improvement in health status , as quantified in an appropriate questionnaire, such as the St George's Respiration Questionnaire (for example, a 4-point improvement score) In another example, for the treatment of arthritis (for example, inflammatory arthritis (for example, rheumatoid arthritis) )), a sufficient amount can be administered to achieve an improvement of 20 percent or more in at least three of the measures established by the American College of Rheumatology (Felson et al., Arthptis and Rheumatism, 38727-735 (1995)). The amounts needed to achieve this dosage will depend on the severity of the disease and the general condition of the patient, including age, sex, weight, and sex. The patient's general immune system (for example, the state of the patient's immune system) Based on these and other appropriate criteria, the skilled clinician can determine the appropriate amount of ligand to be administered. Generally, the amount may be in the range of 0005 to 50 milligrams of ligand per kilogram of body weight, more commonly doses of 005 to 20 milligrams / kilogram / dose being used For prophylactic applications, compositions containing the present ligands or cocktails thereof can also be administered in dosages similar or slightly lower, to prevent, inhibit, or delay the establishment of the disease (eg, to sustain remission or passivity, or to prevent the acute phase). The skilled clinician may determine the appropriate dosage range to treat, suppress , or prevent the disease The ligand of the invention can be administered up to four times a day, twice a week, once a week, once every two weeks, once a month, or once every two months, in a dose, for example, of about 10 micrograms / kilogram to about 80 milligrams / kilogram, of about 100 micrograms / -kilogram to about 80 milligrams / kilogram, of about 1 micrograms / kilogram to about 80 milligrams / kilogram, of about 1 micrograms / kilogram to approximately 70 milligrams / kilogram, from about 1 micrograms / kilogram to about 60 milligrams / kilogram, from about 1 microgram / kilogram to about 50 milligrams / kilogram, of about 1 microgram / -kilogram to about 40 milligrams / kilogram, from about 1 microgram / kilogram to about 30 milligrams / kilogram, from about 1 micrograms / kilogram to about 20 milligrams / kilogram, from about 1 micrograms / kilogram to about 10 milligrams / kilogram, from about 10 micrograms / kilogram to about 10 milligrams / kilogram, of about 10 micrograms / -kilogram to approximately 5 milligrams / kilogram, of about 10 micrograms / kilogram to about 2.5 milligrams / kilogram, of about 1 milligram / kilogram, of about 2 milligrams / kilogram, of about 3 milligrams / kilogram, of about 4 milligrams / kilogram, of about 5 milligrams / kilogram , of about 6 milligrams / kilogram, of about 7 milligrams / kilogram, of about 8 milligrams / kilogram, of about 9 milligrams / kilogram, or of about 10 milligrams / kilogram. In particular embodiments, the ligand is administered to treat, suppress, or prevent a chronic inflammatory disease once every two weeks or once a month, in a dose of about 2 micrograms / kilogram to about 10 milligrams / kilogram (eg, about 10 micrograms / kilogram, about 1 00 micrograms / kilogram, approximately 1 milligram / kilogram, approximately 2 milligrams / kilogram, approximately 3 milligram bouquets / kilogram, approximately 4 milligrams / kilogram, approximately 5 milligrams / kilogram, approximately 6 milligrams / kilogram, approximately 7 milligrams / kilogram, approximately 8 milligrams / kilogram, approximately 9 milligrams / kilogram, or approximately 10 milligrams / kilogram) The treatment or therapy carried out using the compositions described herein is considered "effective" and one or more symptoms are reduced (for example, by at least 1 0 percent, or at least one point on the scale of evaluation clinical), in relation to these symptoms present before treatment, or in relation to these symptoms in an individual (human or animal model) not treated with the composition or other appropriate control. The symptoms will obviously vary depending on the disease or the targeted disorder, may be measured by an ordinarily skilled clinician or technician These symptoms can be measured, for example, by monitoring the level of one or more biochemical indicators of the disease or disorder (eg, the levels of an enzyme or metabolite correlated with the disease, the number of affected cells, etc.), by monitoring physical manifestations (eg, inflammation, tumor size, etc.), or by an accepted clinical assessment scale, for example, the Scale of State of Expanded Disability (for sclerosis multiple), the Irvine Bowel Inflammatory Disease Questionnaire (the 32-point evaluation evaluates the quality of life with respect to bowel function, systemic symptoms, social function, and emotional state - the score is in the range of 32 to 224, with the highest grades indicating a better quality of life), the Quality Rheumatoid Arthritis Scale of Life, the measures established by the American College of Rheumatology, or another scale of accepted clinical evaluation, as is known in this field. A sustained reduction (for example, a day or more, preferably longer) in the symptoms of the disease or disorder by at least 10 percent, or by one or more points on a given clinical scale, indicates a treatment "effective" In a similar manner, prophylaxis carried out using a composition as described herein, is "effective" if the establishment or severity of one or more symptoms in relation to, is delayed, reduced, or eliminated. these symptoms in a similar individual (human or animal model) not treated with the composition A composition containing a ligand or a cocktail thereof according to the present invention, can be used in prophylactic and therapeutic settings to aid in the alteration, inactivation , annihilation, or removal of a selected target cell population in a mammal In addition, the selected repertoires of pohpeptides described herein may be used extracorporeally or selectively to kill annihilate, consuming, or otherwise effectively removing a population of target cells from a heterogeneous collection of cells. The blood of a mammal can be combined extracorporeally with the gandos, for example antibodies, cell surface receptors, or protein binding proteins. the same, wherein the unwanted cells are annihilated or otherwise removed from the blood, to be returned to the animal according to conventional techniques. A composition containing an antagonist (e.g., a ligand) according to the present invention, is can be used in prophylactic and therapeutic settings to help the alteration, inactivation, annihilation, or removal of the population of selected target cells in a mammal In one embodiment, the invention is a method for the treatment, suppression, or prevention of a chronic inflammatory disease, which comprises administering to a mammal in need, a therapeutically effective dose or amount of A Ligand of the Invention In one embodiment, the invention is a method for the treatment, suppression, or prevention of arthritis (e.g., inflammatory arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, and spondyloarthropathies, such as ankylosing spondylitis). , Reactive Arthritis, Reiter's Syndrome, Sopatic Arthritis, Sopatic Spondylitis, Enteropathic Arthritis, Enteropathic Spondylitis, Spondyloarthropathy of Juvenile Establishment, and Non-differentiated Spondyloarthropathy)), which comprises administering to a mammal in need, a therapeutically effective dose or amount of a ligand of the invention In another embodiment, the The invention is a method for the treatment, suppression, or prevention of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), which comprises administering to a mammal in need, a therapeutically effective dose or amount of a ligand of the invention EXAMPLES Example 1 Methods Selections and Tracking For the primary selections, a library was extended 4G-K2 of dAbs VK against the IL-1R1-Fc fusion protein (Axxora, Nottingham, United Kingdom). The domain antibodies from the primary selection were subjected to three additional rounds of selection Round 1 was carried out using magnetic beads coated with G protein (Dynal, Norway), and 100 nM IL-1R1-Fc; Round 2 was carried out using human anti-IgG beads (Novagen, Merck Biosciences, Nottingham, United Remo), and 10 nM IL-1R1-Fc, and round 3 was carried out using G-protein beads and IL-1 beads. 1R1-Fc 1 nM (Hendepkx et al., Selection of antibodies against biotylated antigens Antibody Phage Display, Methods and protocols, Ed. O'Bpen and Atkm, Humana Press (2002)). The elution in each stage was with 1 milligram / milliliter of trypsin-phosphate regulated serum (PBS). For the affinity maturation selections, the previous method was used, but with the following modifications, two rounds of selection were carried out using G protein beads, round 1 using 1 nM IL-1R1-Fc, and round 2 using 100 pM IL-1R1-Fc. Phage vectors from the selection productions (rounds 2 and 3) were isolated by plasmid preparations (Qiagen), and dAb inserts were released by restriction digestion with Sal and NET I.
These inserts were ligated into a phage display vector (Sal \ INot I pDOM5 cut), and were used to transform strain E. coli HB2151 for soluble expression and tracing of the dAbs. Linkage Assay of the Supernatant Receptor (RBA). Individual transformed E. coli colonies were collected in 96-well plates containing 2xTY supplemented with 100 micrograms / milliliter of carbenicillin, and 0.1 percent (w / v) glucose, grown at 37 ° C to an ~ OD600 = 0.9 , and were induced with 1 mM IPTG. The supernatants of the nocturnal inductions at 30 ° C were screened in a receptor binding assay to determine the ability to inhibit the binding of I L-1β to the I L-1 R 1 captured on an ELISA plate. Briefly stated, the MaxiSorp ™ immunoassay plates (Nunc, Denmark) were incubated overnight with an anti-IL-1 R 1 mouse monoclonal antibody (R & D Systems, Minneapolis, USA). The wells were washed with phosphate-buffered saline (PBS) containing 0.1 percent (volume / volume) Tween 20, and then blocked with 1 percent (w / v) bovine serum albumin in phosphate-buffered serum before incubate with the recombinant IL-1R1 (500 nanograms / milliliter, R &D Systems). The supernatants of the E. coli culture containing the dAbs to be screened were placed in the washed wells of the assay plate, the plate was incubated for 30 minutes at room temperature, then IL-1β (4 nanograms) was added. / milliliter, R &D Systems) to each well, and mixed. The IL-1ß binding is detected using biotinylated anti-1 L-1β antibody (R & D Systems), followed by anti-biotin antibody labeled with peroxidase (Stratech, Soham, UK), and then incubation with 3.3 'substrate, 5,5'-tetramet? L-benz? D? Na (TMB) (KPL, Gaithersburg, USA). The reaction was stopped by the addition of HCl, and the absorbance was read at 450 nanometers. The activity of the dAb anti-l L-1 R1 caused a decrease in the binding of I L-1β, and consequently, a decrease in the absorbance, comparing with the control of only IL-1β. Cell Assay Isolated dAbs were tested for their ability to inhibit IL-1-induced IL-1 release from cultured MRC-5 cells (ATCC, Catalog Number CCL-171) Briefly stated, they were placed 5,000 MRC-5 cells were harvested in an RPMI medium in the well of a tissue culture microtiter plate, and mixed with IL-1a or β (R & D Systems, final concentration of 200 picograms / milliliter), and a dilution of the dAb to be tested The mixture was incubated overnight at 37 ° C, and the IL-8 released by the cells in the culture medium was quantified in an ELISA (DuoSet®, R &D Systems). dAb ant? -IL-R1 caused a decrease in the binding of IL-1, and a corresponding reduction in the release of IL-8 Human Whole Blood Test. Human whole blood was incubated with a series of dilution of the dAb that went to test, and the mixture was incubated for 30 minutes at 37 ° C / 02 to 5 percent. Next, IL-1 at or I L-1β was added at 270 or 900 pM (final concentration), and then the mixture was incubated at 37 ° C / 5% C02 for an additional 20 hours. The blood was then centrifuged (500 x g, 5 minutes), and IL-6 released to the supernatant was quantified in an ELISA (DuoSet®, R &D Systems). The activity of the anti-l L-1 R 1 dAb caused a decrease in IL-1 binding and a corresponding reduction in the release of IL-6. Offset Tracing These experiments were carried out on a BIACORE 3000 surface plasmon resonance instrument, using a CM5 (Biacore) chip coupled with -600 RU of IL-1R1 (R &D Systems). The anates were passed over the flow cell coated with IL-1R1, with the reference in line against a control flow cell, at a flow rate of 30 microliters / minute in the execution regulator of HBS-EP (Biacore ). Ten microliters of supernatant containing the soluble dAb were diluted to 11 in the execution buffer, injected (Kinject) at a flow rate of 10 microliters / mmuto, and allowed to dissociate in the regulator. The clones with better phase shifts compared with the parental clones were identified visually, or by means of a measurement using the BIAevaluation software version 41 IL-1ra Competition by Surface Plasmon Resonance. These experiments were carried out in an instrument of surface plasmon resonance BIACORE 3000, using a CM5 chip (Biacore) coupled with -600 RU of IL-1R1 (R &D Systems). The analytes were passed over the flow cell coated with antigen, with the reference in line against a control flow cell, at a flow rate of 30 microliters / minute in the execution buffer of HBS-EP (Biacore). IL-1ra (100 nM, R &D Systems) was injected for 60 seconds, followed immediately by a 60-second injection of the 200 nM DOM4-130-3 dAb, or 100 nM IL-1a, using the co-ease facility. -injection. Competition ELISA of IL-1ra. A MaxiSorp ™ immunoassay plate (Nunc, Denmark) was coated overnight with 1 microgram / milliliter of IL-1R1-FC, then washed three times with phosphate-buffered serum, before being blocked with 1 percent Tween 20 (volume / volume) in serum regulated with phosphate. The plates were washed again, before the addition of I L-1 to 500 pM mixed with the dilution series of DOM4-130-3 or IL-1 a. The binding of IL-1 ra to the receptor was detected using the biotinylated anti-IL-1ra antibody (DuoSet®, R & amp;; D Systems), followed by streptavidin-HRP, and was developed with the 3,3 ', 5,5'-tetramethyl-benzidine (TMB) substrate (KPL, Gaithersburg, USA) as described above. The competition with I L-1 ra for the link with I L-1 R 1 was indicated by a reduction in A450, compared to the control wells that did not contain I L-1 ra. Construction of the Phage Library of Maturation by Affinity Two types of libraries were built: Diversified CDRs and libraries susceptible to error For the first type of library, polymerase chain reactions were carried out, using degenerate oligonucleotides containing the NNK or NNS codons, to diversify the positions required in the dAb to mature by affinity. the assembly polymerase chain reaction was used to generate a full-length diversified insert. For the library susceptible to error, the DNA of the plasmid encoding the dAb as matured by affinity, was amplified by chain reaction of the pohmerase, using the GeneMorph® Random Mutagenesis kit (Stratagene). The inserts produced by any method were digested with Sal I and Not I, and were used in a ligation reaction with the cut phage vector This ligation was then used to transform the TB1 strain of E coli by electroporation, and the transformed cells were applied to agar 2xTY containing 15 micrograms / tetracycline milliliter, providing library sizes of > 1x108 clones Primary Screening and Screening Results Primary phage selections were carried out using a 4G-K2 library, and the productions were subcloned into a soluble expression vector (pDOM5). The dAb clones that inhibited IL-1 binding with the I L-1 R 1 were identified by RBA of the supernatant, then expressed, purified by L protein, and tested for their ability to inhibit the release of IL-8 induced by IL-1 in an MRC-5 cell assay. Figure 1 shows a dose response curve for anti-IL-IRI dAbs. DOM4-122 and DOM4-129 in this cellular assay. The neutralizing dose 50 (ND50) for each dAb was about 1 μM in the DOM4-122 assay and DOM4-129 have the same amino acid sequence in the CDRs 1 and 2, and have two of five identical amino acid residues in the CDR3 , and, consequently, they were predicted to bind to the same epitope on the receptor. Maturation by Affinity Maturation of Stage I Using DOM4-122 as a template, a maturation library with diversity was constructed that encoded all 20 amino acids in the positions 28, 30, 31, 92 and 93. In parallel, DOM4-129 matured by affinity by mutagenicity of polymerase chain reaction susceptible to error. The resulting phage libraries were used in soluble selections against IL-IRI-Fc. The selectable productions of rounds 2 and 3 were cloned into the phage display vector (pDOM5), the dAbs were expressed in E. coli, and the dAbs were screened into the expression supernatants to improve the phase shifts, compared to the dAb progenitor Clones with better phase shifts were expressed, purified, and tested in the MRC-5 / IL-8 assay. Figure 2 illustrates a dose response curve for the improved variants DOM4-122-6 and DOM4-129-1, which had both ND50 values of approximately 10 nM.
Maturation of Stage II Affinity maturation of Stage I of anti-IL-1R1 dAb DOM4-122 (ND50 approximately 1 μM) by re-diversification of CDRs 1 and 3, provided DOM-4-122-6 (approximately 10 nM) The maturation of DOM4-129 (approximately 1 μM) by polymerase chain reaction susceptible to error produced DOM-4-129-1 (approximately 10 nM) DOM4-129-1 and DOM4-122- 6 obtained a mutation, L46F, in common during maturation, whereas DOM4-129-1 has an additional mutation, S56R. Both changes were frequently found in the clones isolated from the maturation selections and, therefore, were introduced the S56R mutation in DOM4-122-6, providing the DOM4-122-23 This combination mutant dAb has an ND50 of approximately 1 nM (Figure 2) An additional point mutation, K45M, gained in both DOM4-122 and DOM4- 129, proved not to be essential when reverted to the germ line on DOM4-122-23, providing DOM4-122-24 Epitope Specificity of the dAbs. In order to determine the epitopic specificity of anti-1 L-1 R 1 dAbs, competitive binding assays were carried out In a study using the surface plasmon resonance instrument BIACORE, the I L-1 ra was injected a chip coupled with IL-1R1, and immediately afterwards DOM4-122-23 or IL-1a was injected The results are presented in Figures 3A and 3B Figure 3B shows that DOM4-122-23 bound to IL-1R1 which had already bound the I-L-1 ra When an injection of I L-1 ra was followed by an injection of IL-1a, two molecules known to be competed for the binding to the receptor, IL-1a could not bind to the receptor either (Figure 3B) The results were confirmed using a competitive ELISA, where the binding of IL-1ra was determined with IL-1R1 in the presence of DOM4-122-23 or IL-1a (in a series of concentrations) The ELISA results showed that DOM4-122-23 did not inhibit the binding of IL-1ra (500 pM) with IL-1R1, even when it was present in concentrations up to 1 μM, where IL-1a did inhibit the binding of I L-1 ra with IL-1R1 (Figure 4) The results confirmed that, although DOM4-122-23 inhibits the binding of IL-1 with the IL-1R1, does not compete with IL-1ra for the binding with IL-1R1 Example 2. Protease stability. Protease Stability The dAbs and the ligands comprising dAbs are useful for the treatment of a variety of conditions, such as inflammatory conditions. In addition, as described herein, the half-life of dAbs and ligands can be made tailored, for example, by PEGylation Accordingly, dAbs and ligands can be administered, for example, systematically (e.g., PEGylated dAb to treat arthritis) or locally (e.g., dAb monomer to treat chronic obstructive pulmonary disease ) We investigated the stability of two dAbs that bind to IL-1R1 for the action of elastase or trypsin. Both proteases are found naturally at low levels within the lung, but under conditions such as chronic obstructive pulmonary disease, they can be elevate protease levels, such as elastase In the study, dAb monomers DOM4-130-54 were used, and a variant of DOM4-130-54 containing a point mutation that provides a cistern residue for the specific binding of PEG A solution of 1 milligram / milliliter of DOM4-130-54 in phosphate-regulated serum was incubated with either trypsin or elastase at 004 weight percent / weight (human sputum leukocyte elastase purchased from Elastin Products Company Ine) Then the dAb / protease mixture was incubated at 30 ° C, and samples were taken at defined time intervals (0, 1, 3, and 24 hours) for the SDS-PAGE analysis. At the given time points, the reaction was from had by adding SDS-PAGE charge regulator (concentrated supply solution to x10), followed by instant freezing of samples in liquid nitrogen Samples were analyzed by SDS-PAGE, and protein bands were visualized to reveal a curve of time for the degradation of protease from dAbs Results Two forms of DOM4-130-54 were tested to determine their stability to the action of elastase, the monomer expressed by E. coli, and the designed variant of cysteine P80C expressed from P. pastons. The P80C point mutation of DOM4-130-54 provides a cysteine residue for the specific binding of PEG. The time course for elastase degradation revealed that even after 24 hours, DOM4-130-54 shows no signs of degradation. The results also revealed that the introduction of the P80C mutation had no effect on the stability of the protein, compared with the DOM4-130-54 These results indicate that the tertiary structure of the P80C variant does not differ substantially from the tertiary structure of DOM4-130-54. The stability of monomeric dAb DOM4-130-54 in the presence of trypsin was also tested. The course of time for the degradation of trypsin revealed that the DOM4-130-54 was stable for at least three hours, and only degradation was seen at the 24 hour time point. The results of this study revealed that dAbs are stable and resistant to degradation mediated by elastase or by trypsin. The demonstrated stability of dAbs to degradation by protease indicates that dAbs can be administered m live, and will remain functional for a sufficient amount of time to produce significant biological effects. For example, the results indicate that, when the dAbs are administered to the lung, they will be resistant to degradation by the protease, and therefore, will be functional for a period of time. period of time that is sufficient to produce significant biological effects (for example, linkage and inhibition of the activity of a target protein, such as IL-1R1). Although this invention has been particularly shown and described with reference to the preferred embodiments thereof, it will be understood by those skilled in the art that different changes may be made in the form and in the details thereof, without departing from the scope of the invention. invention covered by the appended claims.

Claims (67)

  1. CLAIMS 1 A domain antibody monomer (dAb) that has binding specificity for the interferon-1-type 1 receptor (IL-1), and that inhibits the binding of the etherleuclease-1 (IL-). 1) with the receptor, but does not inhibit the binding of the interferon receptor antagonist na-1 (I L-1 ra) with IL-1R1. The dAb monomer of claim 1, wherein the aforementioned IL-1 is selected from the group consisting of? -terleucine-1 a (IL-1a) e? Nterleuc? Na-1? (IL-1? ). 3. The dAb monomer of claim 1, wherein said dAb monomer inhibits the binding of IL-1 to IL-1R1 with an IC50 that is not greater than about 1 μM. The dAb monomer of claim 1, wherein this dAb monomer inhibits the IL-1-induced release of the nterleucin-8 from the MRC-5 cells (ATCC Accession Number CCL-171) , in an in vitro assay, with an ND50 which is < 1 μM. 5. The dAb monomer of claim 4, wherein this dAb monomer inhibits the IL-1-induced release of the nterleucin-8 from the MCR-5 cells (ATCC Accession Number CCL-171). ), in an in vitro assay, with an ND50 which is < 1 μM. 6. The dAb monomer of claim 1, wherein this dAb monomer inhibits the release induced by IL-1 of the ether-6 in a whole blood assay, with an ND50 which is < 1 μM 7 The dAb monomer of any of claims 1 to 6, wherein one or more of the framework regions (FR) in this dAb monomer comprises (a) the amino acid sequence of a region of human structure, ( b) at least 8 contiguous amino acids of the amino acid sequence of a region of human structure, or (c) an amino acid sequence encoded by a genetic segment of the human germline antibody, where these structure regions are as defined Kabat. The dAb monomer of claim 7, wherein the amino acid sequences of one or more structure regions in this dAb monomer are the same as the amino acid sequence of a corresponding structure region encoded by a genetic segment of the line human germline, or the amino acid sequences of one or more of these structure regions collectively comprise up to five amino acid differences relative to the corresponding structure regions encoded by a genetic segment of the human germline antibody 9 The dAb monomer of Claim 7, wherein the amino acid sequences of FR1, FR2, FR3, and FR4 in this dAb monomer are the same as the amino acid sequences of the corresponding structure regions encoded by a genetic segment of human germline antibody, or the amino acid sequences of FR1, FR2, FR3, and FR4 collectively contain up to 10 amino acid differences relative to the corresponding structure regions encoded by a genetic segment of antibody from the human germ line The dAb monomer of claim 7, wherein the dAb monomer comprises the FR1, FR2, and FR3 regions, and the amino acid sequence of these FR1, FR2, and FR3 are the same as the amino acid sequences of the regions of corresponding structures encoded by a genetic segment of the human germline antibody. 11. The dAb monomer of any of claims 7 to 10, wherein the genetic segment of said human germline antibody is DPK9 and JK1. 12. The dAb monomer of claim 1, wherein this dAb monomer competes for binding with IL-1R1, with a dAb selected from the group consisting of DOM4-122-23 (SEQ ID NO: 1), DOM4- 122-24 (SEQ ID NO: 2), DOM4-122 (SEQ ID NO: 95), DOM4-122-1 (SEQ ID NO: 96), DOM4-122-2 (SEQ ID NO: 97), DOM4-122-3 (SEQ ID NO: 98), DOM4-122-4 (SEQ ID NO: 99), DOM4-122-5 (SEQ ID NO: 100), DOM4-122-6 (SEQ ID NO-, 101), DOM4-122-7 (SEQ ID NO: 102), DOM4-122-8 (SEQ ID NO: 103), DOM4-122-9 (SEQ ID NO: 104), DOM4-122-10 (SEQ ID NO: 105), DOM4-122-11 (SEQ ID NO: 106), DOM4-122-12 (SEQ ID NO: 107), DOM4-122-13 (SEQ ID NO: 108), DOM4-122-14 (SEQ ID NO: 109 DOM4-122-15 (SEQ ID NO: 110), DOM4-122-16 (SEQ ID NO: 111 DOM4- 122-17 (SEQ ID NO: 112), DOM4-122-18 (SEQ ID NO: 113 DOM4- 122-19 (SEQ ID NO: 114), DOM4-122-20 (SEQ ID NO: 115 DOM4- 122-21) (SEQ ID NO: 116), DOM4-122-22 (SEQ ID NO: 117 DOM4- 122-25 (SEQ ID NO: 118), DOM4-122-26 (SEQ ID NO: 119 DOM4- 122-27 (SEQ ID NO: 120), DOM4-122-28 (SEQ ID NO: 121 DOM4-122-29 (SEQ ID NO: 122), DOM4-122-30 (SEQ ID NO: 123 DOM4- 122-31) (SEQ ID NO: 124), DOM4-122-32 (SEQ ID NO: 125 DOM4--122-33 (SEQ ID NO -126), DOM4-122-34 (SEQ ID NO: 127 DOM4--122-35 (SEQ ID NO: 128), DOM4-122-36 (SEQ ID NO: 129 DOM4--122-37 (SEQ ID NO: 130), DOM4-122-38 (SEQ ID NO: 131 DOM4--122-39 (SEQ ID NO-.132), DOM4-122-40 (SEQ ID NO: 133 DOM4--122-41 (SEQ ID NO: 134), DOM4-122-42 (SEQ ID NO: 135 DOM4--122-43 (SEQ ID NO: 136), DOM4-122-44 (SEQ ID NO: 137 DOM4--122-45 (SEQ ID NO: 138), DOM4-122-46 (SEQ ID NO: 139 DOM4--122-47 (SEQ ID NO: 140), DOM4-122-48 (SEQ ID NO -141 DOM4--122-49 (SEQ ID NO-.142) DOM4-122-50 (SEQ ID NO: 143 DOM4--122-51 (SEQ ID NO: 144), DOM4-122-52 (SEQ ID NO: 145 DOM4--122-54 (SEQ ID NO -146) DOM4-122-55 (SEQ ID NO: 147 DOM4--122-56 (SEQ ID NO: 148), DOM4-122-57 (SEQ ID NO: 149 DOM4--122-58 (SEQ ID NO: 150), DOM4-122-59 (SEQ ID NO: 151 DOM4--122-60 (SEQ ID NO: 152), DOM4-122-61 (SEQ ID NO: 153 DOM4--122-62 (SEQ ID NO: 154), DOM4-122-63 (SEQ ID NO: 155 DOM4--122-64 (SEQ ID NO: 156), DOM4-122-65 (SEQ ID NO: 157 DOM4 -122-66 (SEQ ID NO: 158), DOM4-122-67 (SEQ ID NO: 159), DOM4-122-68 (SEQ ID NO: 160), DOM4-122-69 (SEQ ID NO: 161), DOM4-122 -70 (SEQ ID NO: 162), DOM4-122-71 (SEQ ID NO: 163), DOM4-122-72 (SEQ ID NO: 164), DOM4-122-73 (SEQ ID NO: 165), DOM4 -1 (SEQ ID NO: 8), DOM4-2 (SEQ ID NO: 9), DOM4-3 (SEQ ID NO: 10), DOM4-4 (SEQ ID NO: 11), DOM4-5 (SEQ ID NO: 12), DOM4-6 (SEQ ID NO: 13), DOM4-7 (SEQ ID NO: 14), DOM4-8 (SEQ ID NO: 15) ), DOM4-9 (SEQ ID NO: 16), DOM4-10 (SEQ ID NO: 17), DOM4-11 (SEQ ID NO: 18), DOM4-12 (SEQ ID NO: 19), DOM4-13 ( SEQ ID NO: 20), DOM4-14 (SEQ ID NO: 21), DOM4-15 (SEQ ID NO: 22), DOM4-20 (SEQ ID NO: 23), DOM4-21 (SEQ ID NO: 24), DOM4-22 (SEQ ID NO: 25), DOM4-23 (SEQ ID NO: 26), DOM4-25 (SEQ ID NO: 27), DOM4 -26 (SEQ ID NO: 28), DOM4-27 (SEQ ID NO: 29), DOM4-28 (SEQ ID NO: 30), DOM4-29 (SEQ ID NO: 31), DOM4-31 (SEQ ID NO. : 32), DOM4-32 (SEQ ID NO: 33), DOM4-33 (SEQ ID NO: 34), DOM4-34 (SEQ ID NO: 35), DOM4-36 (SEQ ID NO: 36), DOM4-37 (SEQ ID NO: 37), DOM4-38 (SEQ ID NO: 38), DOM4-39 (SEQ ID NO: 39 ), DOM4-40 (SEQ ID NO: 40), DOM4-41 (SEQ ID NO: 41), DOM4-42 (SEQ ID NO.42), DOM4-44 (SEQ ID NO: 43), DOM4-45 ( SEQ ID NO: 44), DOM4-46 (SEQ ID NO: 45), DOM4-49 (SEQ ID NO: 46), DOM4-50 (SEQ ID NO: 47), DOM4-74 (SEQ ID NO: 48), DOM4-75 (SEQ ID NO: 49), DOM4-76 (SEQ ID NO: 50), DOM4-78 (SEQ ID NO: 51), DOM4-79 (SEQ ID NO: 52), DOM4-80 (SEQ ID NO: 53), DOM4-81 (SEQ ID NO: 54), DOM4-82 (SEQ ID NO: 55), DOM4 -83 (SEQ ID NO: 56), DOM4-84 (SEQ ID NO: 57), DOM4-85 (SEQ ID NO: 58), DOM4-86 (SEQ ID NO: 59), DOM4-87 (SEQ ID NO: 60), DOM4-88 (SEQ ID NO: 61), DOM4-89 (SEQ ID NO: 62), DOM4 -90 (SEQ ID NO: 63), DOM4-91 (SEQ ID NO: 64), DOM4-92 (SEQ ID NO: 65), DOM4-93 (SEQ ID NO: 66), DOM4-94 (SEQ ID NO. : 67), DOM4-95 (SEQ ID NO: 68), DOM4-96 (SEQ ID NO: 69), DOM4-97 (SEQ ID NO: 70), DOM4-98 (SEQ ID NO: 71), DOM4-99 (SEQ ID NO: 72), DOM4-100 (SEQ ID NO: 73), DOM4-101 (SEQ ID NO: 74) ), DOM4-102 (SEQ ID NO: 75), DOM4-103 (SEQ ID NO: 76), DOM4-104 (SEQ ID NO: 77), DOM4-105 (SEQ ID NO: 78), DOM4-106 ( SEQ ID NO: 79), DOM4-107 (SEQ ID NO: 80), DOM4-108 (SEQ ID NO: 81), DOM4-109 (SEQ ID NO: 82), DOM4-110 (SEQ ID NO: 83), DOM4-111 (SEQ ID NO: 84), DOM4-112 (SEQ ID NO: 85), DOM4-113 (SEQ ID NO: 86), DOM4-114 (SEQ ID NO: 87), DOM4-115 (SEQ ID NO: 88), DOM4-116 (SEQ ID NO.89), DOM4-117 (SEQ ID NO: 90), DOM4 -118 (SEQ ID NO: 91), DOM4-119 (SEQ ID NO: 92), DOM4-120 (SEQ ID NO: 93), DOM4-121 (SEQ ID NO: 94), DOM4-123 (SEQ ID NO: 166), DOM4-124 (SEQ ID NO: 167) DOM4-125 (SEQ ID NO: 168), DOM4- 126 (SEQ ID NO: 169), DOM4-127 (SEQ ID NO: 170), DOM4-128 (SEQ ID NO: 171), DOM4-129 (SEQ ID NO: 172), DOM4-129-1 (SEQ ID NO: 173.) DOM4-129-2 (SEQ ID NO: 174), DOM4-129-3 (SEQ ID NO: 175), DOM4-129-4 (SEQ ID NO: 176), DOM4-129-5 (SEQ ID NO: 177), DOM4-129-6 (SEQ ID NO: 178), DOM4-129-7 ( SEQ ID NO: 179), DOM4-129-8 (SEQ ID NO: 180), DOM4-129-9 (SEQ ID NO: 181), DOM4-129-10 (SEQ ID NO: 182), DOM4-129- 11 (SEQ ID NO: 183), DOM4-129-12 (SEQ ID NO: 184), DOM4-129-13 (SEQ ID NO 185), DOM4-'129-14 (SEQ ID NO: 186), DOM4-129-15 (SEQ ID NO 187), DOM4-129-16 (SEQ ID NO: 188), DOM4-129-17 (SEQ ID NO 189), DOM4-129-18 (SEQ ID NO: 190), DOM4-129-19 (SEQ ID NO 191), DOM4-129-20 (SEQ ID NO: 192), DOM4-129-21 (SEQ ID NO 193), DOM4-129-22 (SEQ ID NO: 194), DOM4-129-23 (SEQ ID NO 195), DOM4-129-24 (SEQ ID NO: 196), DOM4-129-25 (SEQ ID NO 197), DOM4-129-26 (SEQ ID NO-.198), DOM4-129-27 (SEQ ID NO 199), DOM4-129-28 (SEQ ID NO: 200), DOM4-129-29 (SEQ ID NO: 201), DOM4-129-31 (SEQ ID NO: 202), DOM4-129-32 (SEQ ID NO: 203), DOM4-129-33 (SEQ ID NO: 204), DOM4-129-34 (SEQ ID NO 205), DOM4-129-35 (SEQ ID NO: 206), DOM4-129-37 (SEQ ID NO: 207), DOM4-129-38 (SEQ ID NO: 208), DOM4-129-39 (SEQ ID NO.209) DOM4-129-40 (SEQ ID NO: 210), DOM4-129-41 (SEQ ID NO: 211) DOM4-129-42 (SEQ ID NO: 212), DOM4-129-43 (SEQ ID NO: 213) DOM4-129-44 (SEQ ID NO: 214), DOM4-131 (SEQ ID NO 347) DOM4-132 (SEQ ID NO: 348), and DOM4-133 (SEQ ID NO: 349) 13. The dAb monomer of claim 12, wherein this dAb monomer comprises an amino acid sequence having an amino acid sequence identity of at least about 90 percent with the amino acid sequence of a dAb selected from the group consisting of DOM4-122-23 (SEQ ID NO: 1), DOM4-122-24 (SEQ ID NO: 2), DOM4-122 (SEQ ID NO: 95), DOM4-122-1 (SEQ ID NO: 96), DOM4-122-2 (SEQ ID NO: 97), DOM4-122-3 (SEQ ID NO: 98), DOM4- 122-4 (SEQ ID NO.99), D OM4-122-5 (SEQ ID NO: 100), DOM4-122-6 (SEQ ID NO: 101), DOM4- 122-7 (SEQ ID NO: 102) , DOM4-122-8 (SEQ ID NO: 103), DOM4-122-9 (SEQ ID NO: 104), DOM4-122-10 (SEQ ID NO: 105), DOM4-122-11 (SEQ ID NO: 106 DOM4-122-12 (SEQ ID NO: 107), DOM4-122-13 (SEQ ID NO: 108 DOM4-122-14 (SEQ ID NO: 109), DOM4-122-15 (SEQ ID NO: 110 DOM4- 122-16 (SEQ ID NO: 111), DOM4-122-17 (SEQ ID NO: 112 DOM4- 122- 18 (SEQ ID NO: 113), DOM4-122-19 (SEQ ID NO: 114 DOM4- 122-20 (SEQ ID NO: 115), DOM4-122-21 (SEQ ID NO-.116 DOM4 -122-22 (SEQ ID NO: 117), DOM4-122-25 (SEQ ID NO: 118 DOM4- 122-26 (SEQ ID NO: 119), DOM4-122-27 (SEQ ID NO: 120 DOM4- 122 28 (SEQ ID NO: 121), DOM4-122-29 (SEQ ID NO: 122 DOM4- 122 30 (SEQ ID NO: 123), DOM4-122-31 (SEQ ID NO: 124 DOM4- 122-32 (SEQ ID NO: 125), DOM4-122-33 (SEQ ID NO -.126 DOM4 -122 -34 (SEQ ID NO: 127), DOM4-122-35 (SEQ ID NO: 128 DOM4- 122 -36 (SEQ ID NO: 129), DOM4-122-37 (SEQ ID NO: 130 DOM4- 122 -38 (SEQ ID NO: 131), DOM4-122-39 (SEQ ID NO: 132 DOM4- 122 -40 (SEQ ID NO: 133), DOM4-122-41 (SEQ ID NO: 134 DOM4- 122 -42 (SEQ ID NO: 135), DOM4-122-43 (SEQ ID NO-.136 DOM4 -122 -44 (SEQ ID NO: 137), DOM4-122-45 (SEQ ID NO: 138 DOM4 -122 -46 (SEQ ID NO: 139), DOM4-122-47 (SEQ ID NO: 140 DOM4 -122 -48 (SEQ ID NO: 141), DOM4-122-49 (SEQ ID NO: 142 DOM4 -122 -50 (SEQ ID NO: 143), DOM4-122-51 (SEQ ID NO: 144 DOM4 -122 -52 (SEQ ID NO: 145), DOM4-122-54 (SEQ ID NO: 146 DOM4 -122 -55 (SEQ ID NO: 147), DOM4-122-56 (SEQ ID NO: 148 DOM4 -122 -57 (SEQ ID NO: 149), DOM4-122-58 (SEQ ID NO: 150), DOM4-122-59 (SEQ ID NO: 151), DOM4-122-60 (SEQ ID NO: 152), DOM4-122-61 ( SEQ ID NO: 153), DOM4-122-62 (SEQ ID NO: 154), DOM4-122-63 (SEQ ID NO: 155), DOM4-122-64 (SEQ ID NO: 156), DOM4-122- 65 (SEQ ID NO: 157), DOM4-122-66 (SEQ ID NO: 158), DOM4-122-67 (SEQ ID NO: 159), DOM4-122-68 (SEQ ID NO: 160), DOM4-122-69 (SEQ ID NO: 161), DOM4-122-70 (SEQ ID NO: 162), DOM4-122-71 ( SEQ ID NO: 163), DOM4-122-72 (SEQ ID NO: 164), DOM4-122-73 (SEQ ID NO: 165), DOM4-1 (SEQ ID NO: 8), DOM4-2 (SEQ ID NO: 9), DOM4-3 (SEQ ID NO: 10), DOM4-4 (SEQ ID NO: 11), DOM4-5 (SEQ ID NO: 12), DOM4-6 (SEQ ID NO: 13), DOM4-7 (SEQ ID NO: 14), DOM4-8 (SEQ ID NO: 15), DOM4-9 (SEQ ID NO: 16), DOM4-10 (SEQ ID NO: 17), DOM4-11 (SEQ ID NO: 18), DOM4-12 (SEQ ID NO: 19), DOM4-13 (SEQ ID NO: 20), DOM4-14 (SEQ ID NO: 21), DOM4 -15 (SEQ ID NO: 22), DOM4-20 (SEQ ID NO: 23), DOM4-21 (SEQ ID NO: 24), DOM4-22 (SEQ ID NO: 25), DOM4-23 (SEQ ID NO: 26), DOM4-25 (SEQ ID NO: 27), DOM4-26 (SEQ ID NO: 28), DOM4-27 (SEQ ID NO: 29) ), DOM4-28 (SEQ ID NO: 30), DOM4-29 (SEQ ID NO: 31), DOM4-31 (SEQ ID NO: 32), DOM4-32 (SEQ ID NO: 33), DOM4-33 ( SEQ ID NO: 34), DOM4-34 (SEQ ID NO: 35), DOM4-36 (SEQ ID NO: 36), DOM4-37 (SEQ ID NO: 37), DOM4-38 (SEQ ID NO: 38), DOM4-39 (SEQ ID NO: 39), DOM4-40 (SEQ ID NO: 40), DOM4-41 (SEQ ID NO: 41), DOM4-42 (SEQ ID NO: 42), DOM4-44 (SEQ ID NO: 43), DOM4-45 (SEQ ID NO: 44), DOM4-46 (SEQ ID NO: 45), DOM4 -49 (SEQ ID NO: 46), DOM4-50 (SEQ ID NO: 47), DOM4-74 (SEQ ID NO: 48), DOM4-75 (SEQ ID NO: 49), DOM4-76 (SEQ ID NO: 50), DOM4-78 (SEQ ID NO: 51), DOM4-79 (SEQ ID NO: 52), DOM4 -80 (SEQ ID NO: 53), DOM4-81 (SEQ ID NO: 54), DOM4-82 (SEQ ID NO: 55), DOM4-83 (SEQ ID NO: 56), DOM4-84 (SEQ ID NO. : 57), DOM4-85 (SEQ ID NO: 58), DOM4-86 (SEQ ID NO: 59), DOM4-87 (SEQ ID NO: 60), DOM4-88 (SEQ ID NO: 61), DOM4-89 (SEQ ID NO: 62), DOM4-90 (SEQ ID NO: 63), DOM4-91 (SEQ ID NO: 64) ), DOM4-92 (SEQ ID NO: 65), DOM4-93 (SEQ ID NO: 66), DOM4-94 (SEQ ID NO: 67), DOM4-95 (SEQ ID NO: 68), DOM4-96 ( SEQ ID NO: 69), DOM4-97 (SEQ ID NO: 70), DOM4-98 (SEQ ID NO: 71), DOM4-99 (SEQ ID NO: 72), DOM4-100 (SEQ ID NO: 73), DOM4-101 (SEQ ID NO: 74), DOM4-102 (SEQ ID NO: 75), DOM4-103 (SEQ ID NO: 76), DOM4-104 (SEQ ID NO: 77), DOM4-105 (SEQ ID NO: 78), DOM4-106 (SEQ ID NO: 79), DOM4-107 (SEQ ID NO: 80), DOM4 -108 (SEQ ID NO: 81), DOM4-109 (SEQ ID NO: 82), DOM4-110 (SEQ ID NO: 83), DOM4-111 (SEQ ID NO: 84), DOM4-112 (SEQ ID NO: 85), DOM4-113 (SEQ ID NO: 86), DOM4-114 (SEQ ID NO: 87), DOM4 -115 (SEQ ID NO: 88), DOM4-116 (SEQ ID NO: 89), DOM4-117 (SEQ ID NO: 90), DOM4-118 (SEQ ID NO: 91), DOM4-119 (SEQ ID NO. : 92), DOM4-120 (SEQ ID NO: 93), DOM4-121 (SEQ ID NO: 94), DOM4-123 (SEQ ID NO.166), DOM4-124 (SEQ ID NO: 167) DOM4-125 (SEQ ID NO: 168), DOM4-126 (SEQ ID NO: 169), DOM4-127 (SEQ ID NO: 170) , DOM4-128 (SEQ ID NO: 171), DOM4-129 (SEQ ID NO: 172), DOM4-129-1 (SEQ ID NO: 173,) DOM4-129-2 (SEQ ID NO: 174), DOM4 -129-3 (SEQ ID NO: 175), DOM4-129-4 (SEQ ID NO: 176), DOM4-129-5 (SEQ ID NO: 77), DOM4-129-6 (SEQ ID NO: 178), DOM4-129-7 (SEQ ID NO: 179 DOM4-129-8 (SEQ ID NO: 180 DOM4-129-9 (SEQ ID NO: 181 DOM4- • 129- • 10 SEQ ID NO: 182 DOM4-129-11 (SEQ ID NO: 183 DOM4- • 129- • 12 SEQ ID NO: 184 DOM4-129-13 (SEQ ID NO: 185 DOM4- • 129- • 14 SEQ ID NO: 186 DOM4-129-15 (SEQ ID NO: 187 DOM4- • 129- • 16 SEQ ID NO: 188 DOM4-129-17 (SEQ ID NO: 189 DOM4- • 129- • 18 SEQ ID NO: 190 DOM4-129-19 (SEQ ID NO: 191 DOM4- • 129- • 20 SEQ ID NO: 192 DOM4-129-21 (SEQ ID NO: 193 DOM4- • 129- • 22 SEQ ID NO: 194 DOM4-129-23 (SEQ ID NO: 195 DOM4- • 129- • 24 SEQ ID NO: 196 DOM4-129-25 (SEQ ID NO: 197 DOM4- • 129- • 26 SEQ ID NO: 198 DOM4-129-27 (SEQ ID NO: 199 DOM4- • 129- -28 SEQ ID NO: 200 DOM4-129-29 (SEQ ID NO: 201 DOM4- -129- -31 SEQ ID NO: 202 DOM4-129-32 (SEQ ID NO: 203 DOM4- -129- -33 SEQ ID NO: 204 DOM4-129-34 (SEQ ID NO: 205 DOM4- • 129- -35 SEQ ID NO: 206 DOM4-129-37 (SEQ ID NO: 207 DOM4- -129- -38 SEQ ID NO: 208 DOM4-129-39 (SEQ ID NO: 209 DOM4- -129- -40 SEQ ID NO: 210 DOM4-129-41 (SEQ ID NO: 211 DOM4- -129 '-42 SEQ ID NO: 212) DOM4-129-43 (SEQ ID NO: 213 DOM4-129-44 (SEQ ID NO: 214), DOM4-131 (SEQ ID NO: 347 DOM4-132 (SEQ ID NO: 348), and DOM4-133 (SEQ ID NO: 349 14. The dAb monomer of claim 1, wherein this dAb monomer binds to human IL-1R1 with an affinity (KD) of about 300 nM to about 5 pM, as determined by plasmon resonance. superficial. A ligand comprising a dAb monomer according to any of claims 1 to 14, and a fraction that prolongs the half-life. The ligand of claim 15, wherein the fraction that prolongs the aforementioned half-life is a polyalkylene glycol fraction, serum albumin or a fragment thereof, a transferpna receptor or a transferpna binding portion thereof, or an antibody or an antibody fragment comprising a binding site for a polypeptide that improves life by in vivo The ligand of claim 16, wherein the fraction that prolongs the aforementioned half-life is a fraction of poethylene glycol 18 The ligand of claim 16, wherein the fraction that prolongs the half-life is an antibody or an antibody fragment that comprises a binding site for albumin of serum or for the neonatal Fe receptor. The ligand of claim 18, wherein said antibody or antibody fragment is an antibody fragment, and said antibody fragment is a single variable domain of immunoglobulin 20. The ligand of claim 19, wherein the unique The immunoglobulin variable domain mentioned competes for the binding to human serum albumin, with a dAb selected from the group consisting of DOM7m-16 (SEQ ID NQ-723), DOM7m-12 (SEQ ID NO 724), DOM7m-26 (SEQ ID No. 725), DOM7r-l (SEQ ID No. 726), DOM7r-3 (SEQ ID No. 727), DOM7r-4 (SEQ ID No. 728), DOM7r-5 (SEQ ID NO 729), DOM7r-7 (SEQ ID No. 730), DOM7r-8 (SEQ ID No. 731), DOM7h-2 (SEQ ID No. 732), DOM7h-3 (SEQ ID No. 733), DOM7h-4 (SEQ ID NO 734), DOM7h-6 (SEQ ID NO 735), DOM7h-l (SEQ ID NO 736), DOM7h-7 (SEQ ID No. 737), DOM7h-8 (SEQ ID No. 746), DOM7r-13 (SEQ ID No. 747), DOM7r-14 (SEQ ID NO 748), DOM7h-22 (SEQ ID NO 739), DOM7h-23 (SEQ ID No. 740), DOM7h-24 (SEQ ID No. 741), DOM7h-25 (SEQ ID NO -742), DOM7h-26 (SEQ ID No. 743), DOM7h-21 (SEQ ID No. 744), DOM7h-27 (SEQ ID No. 745), DOM7r-15 (SEQ ID No. 749), DOM7r-16 (SEQ ID No. 750), DOM7r-17 (SEQ ID NO 751), DOM7r-18 (SEQ ID NO 752), DOM7r-19 (SEQ ID NO 753), DOM7r-20 (SEQ ID NO 754), DOM7r-21 (SEQ ID NO 755), DOM7r-22 (SEQ ID NO 756), DOM7r-23 (SEQ ID NO 757), DOM7r-24 (SEQ ID NO 758), DOM7r-25 (SEQ ID NO 759), DOM7r-26 (SEQ ID No. 760), DOM7r-27 (SEQ ID No. 761), DOM7r-28 (SEQ ID No. 762), DOM7r-29 (SEQ ID No. 763), DOM7r-30 (SEQ ID NO 764), DOM7r-31 (SEQ ID NO 765), DOM7r-32 (SEQ ID NO 766), and DOM7r-33 (SEQ ID NO 767) 21 The ligand of claim 20, wherein the single immunoglobulin variable domain mentioned is bound to human serum albumin, and comprises an amino acid sequence having an amino acid sequence identity of at least 90 percent with the amino acid sequence of a dAb selected from the group consisting of DOM7m- 16 (SEQ ID NO: 723), DOM7m-12 (SEQ ID NO: 724), DOM7m-26 (SEQ ID NO: 725), DOM7r-l (SEQ ID NO: 726), DOM7r-3 (SEQ ID NO: 727), DOM7r-4 (SEQ ID NO.728), DOM7r-5 (SEQ ID NO: 729), DOM7r-7 (SEQ ID NO: 730), DOM7r-8 (SEQ ID NO: 731), DOM7h-2 (SEQ ID NO: 732), DOM7h-3 (SEQ ID NO: 733), DOM7h-4 (SEQ ID NO: 734), DOM7h-6 (SEQ ID NO: 735), DOM7h-l (SEQ ID NO: 736), DOM7h-7 (SEQ ID NO: 737), DOM7h-8 (SEQ ID NO: 746), DOM7r-13 (SEQ ID NO: 747), DOM7r-14 (SEQ ID NO: 748), DOM7h-22 (SEQ ID NO: 739), DOM7h-23 (SEQ ID NO: 740), DOM7h-24 (SEQ ID NO: 741), DOM7h -25 (SEQ ID NO: 742), DOM7h-26 (SEQ ID NO: 743), DOM7h-21 (SEQ. ID NO: 744), DOM7h-27 (SEQ ID NO: 745), DOM7r-15 (SEQ ID NO: 749), DOM7r-16 (SEQ ID NO: 750), DOM7r-17 (SEQ ID NO: 751), DOM7r-18 (SEQ ID NO: 752), DOM7r-19 (SEQ ID NO: 753), DOM7r-20 (SEQ ID NO: 754), DOM7r-21 (SEQ ID NO -755), DOM7r-22 (SEQ ID NO: 756), DOM7r-23 (SEQ ID NO.757), DOM7r-24 (SEQ ID NO: 758), DOM7r-25 (SEQ ID NO: 759), DOM7r-26 (SEQ ID NO: 760), DOM7r-27 (SEQ ID NO: 761), DOM7r-28 (SEQ ID NO.762), DOM7r-29 (SEQ ID NO: 763), DOM7r-30 (SEQ ID NO: 764), DOM7r-31 (SEQ ID NO: 765), DOM7r-32 (SEQ ID NO: 766), and DOM7r-33 (SEQ ID NO: 767). 22. A ligand comprising a dAb monomer having binding specificity for IL-1R1, and inhibiting the binding of IL-1 to the receptor, but not inhibiting the binding of I L-1 ra with IL-1R1, wherein this dAb monomer is selected from the group consisting of DOM4-122-23 (SEQ ID NO: 1) and DOM4-122-24 (SEQ ID NO: 2). 23. The ligand of claim 22, wherein this ligand is a dAb monomer. 24. The ligand of claim 22, wherein said ligand is a homodimer, homotrimer, or homo-oligomer of said dAb monomer. 25. The ligand of claim 22, wherein this ligand is a heterodimer, heterotrimer, or hetero-oligomer, and comprises DOM4-122-23 (SEQ ID NO: 1) and DOM4-122-24 (SEQ ID NO: 2) ). 26. The ligand of claim 22, which further comprises a dAb monomer that is linked to the serum albumin. 27. The ligand of claim 26, wherein this dAb monomer that binds with serum albumin, is the DOM7h-8 (SEQ ID NO: 746). 28. The ligand of claim 27, wherein this ligand comprises DOM4-122-23 (SEQ ID NO: 1) and DOM7h-8 (SEQ ID NO: 746), or comprises DOM-122-24 (SEQ ID NO: 2) and DOM7h-8 (SEQ ID NO: 746). 29. A ligand comprising a dAb monomer having binding specificity for IL-1R1, and inhibiting the binding of IL-1 to the receptor, but not inhibiting the binding of I L-1 ra to IL-1R1, and a dAb monomer having binding specificity for TNFR1. 30. The ligand of claim 29, wherein said dAb monomer having binding specificity for IL-1R1, and inhibits the binding of IL-1 and IL-1ra with IL-1R1, competes for binding with IL-1R1 with a dAb selected from the group consisting of DOM4-122- 23 (SEQ ID NO: 1), DOM4-122-24 (SEQ ID NO: 2), DOM4-122 (SEQ ID NO: 95), DOM4-122-1 (SEQ ID NO: 96), DOM4-122- 2 (SEQ ID NO: 97), DOM4-122-3 (SEQ ID NO: 98), DOM4-122-4 (SEQ ID NO: 99), DOM4-122-5 (SEQ ID NO: 100), DOM4-122-6 (SEQ ID NO: 101 DOM4-122-7 (SEQ ID NO: 102), DOM4-122-8 (SEQ ID NO.103 DOM4-122-9 (SEQ ID NO: 104), DOM4-122-10 (SEQ ID NO: 105 DOM4-122-11 (SEQ ID NO 106), DOM4-122-12 (SEQ ID NO: 107 DOM4-122-13 (SEQ ID NO 108), DOM4-122-14 (SEQ ID NO: 109 DOM4-122-15 (SEQ ID NO 110), DOM4-122-16 (SEQ ID NO: 111 DOM4-122-17 (SEQ ID NO 112), DOM4-122-18 (SEQ ID NO: 113 DOM4-122-19 (SEQ ID NO 114), DOM4-122-20 (SEQ ID NO: 115 DOM4-122-21 (SEQ ID NO 116), DOM4-122-22 (SEQ ID NO: 117 DOM4-122-25 (SEQ ID NO 118), DOM4-122-26 (SEQ ID NO: 119 DOM4-122-27 (SEQ ID NO 120), DOM4-122-28 (SEQ ID NO: 121 DOM4-122-29 (SEQ ID NO 122), DOM4-122-30 (SEQ ID NO: 123 DOM4-122-31 (SEQ ID NO 124), DOM4-122-32 (SEQ ID NO: 125 DOM4-122-33 (SEQ ID NO 126), DOM4-122-34 (SEQ ID NO: 127 DOM4-122-35 (SEQ ID NO 128), DOM4-122-36 (SEQ ID NO: 129 DOM4-122-37 (SEQ ID NO 130), DOM4-122-38 (SEQ ID NO: 131 DOM4-122-39 (SEQ ID NO 132), DOM4-122-40 (SEQ ID NO: 133 DOM4-122-41 (SEQ ID NO 134), DOM4-122-42 (SEQ ID NO: 135 DOM4-122-43 (SEQ ID NO: 136), DOM4-122-44 (SEQ ID NO: 137 DOM4-122-45 (SEQ ID NO: 138) DOM4-122 46 SEQ ID NO: 139) DOM4-122-47 (SEQ ID NO: 140) DOM4-122 • 48 SEQ ID NO: 141) DOM4-122-49 (SEQ ID NO: 142) DOM4 - 122 50 SEQ ID NO: 143) DOM4- 122-51 (SEQ ID NO: 144) DOM4- 122 • 52 SEQ ID NO: 145) DOM4- 122-54 (SEQ ID NO: 146) DOM4- 122 • 55 SEQ ID NO: 147) DOM4-122-56 (SEQ ID NO: 148) DOM4-122 • 57 SEQ ID NO: 149) DOM4-122-58 (SEQ ID NO: 150) DOM4- 122-59 SEQ ID NO: 151 ) DOM4-122-60 (SEQ ID NO: 152) DOM4 122-61 SEQ ID NO: 153) DOM4-122-62 (SEQ ID NO: 154) DOM4 122-63 SEQ ID NO: 155) DOM4- 122-64 (SEQ ID NO: 156) DOM4 122 -65 SEQ ID NO: 157) DOM4-122-66 (SEQ ID NO: 158) DOM4 -122 -67 SEQ ID NO: 159) DOM4- 122-68 (SEQ ID NO: 160) DOM4 -122 -69 SEQ ID NO: 161) DOM4-122-70 (SEQ ID NO: 162) DOM4 -122 -71 SEQ ID NO: 163) DOM4- 122-72 (SEQ ID NO: 164) DOM4- 122-73 (SEQ ID NO: 165), DOM4-1 (SEQ ID NO: 8), DOM4-2 (SEQ ID NO: 9), DOM4-3 (SEQ ID NO: 10), DOM4-4 (SEQ ID NO: 11), DOM4-5 (SEQ ID NO: 12), DOM4-6 (SEQ ID NO: 13), DOM4-7 (SEQ ID NO: 14), DOM4-8 (SEQ ID NO: 15), DOM4 -9 (SEQ ID NO: 16), D OM4-10 (SEQ ID NO: 17), DOM4-11 (SEQ ID NO: 18), DOM4-12 (SEQ ID NO: 19), DOM4-13 (SEQ ID NO: 20), DOM4-14 (SEQ ID NO: 21), DOM4-15 (SEQ ID NO: 22), DOM4-20 (SEQ ID NO: 23), DOM4-21 (SEQ ID NO: 24), DOM4-22 (SEQ ID NO: 25), DOM4 -23 (SEQ ID NO: 26), DOM4-25 (SEQ ID NO: 27), DOM4-26 (SEQ ID NO: 28), DOM4-27 (SEQ ID NO: 29), DOM4-28 (SEQ ID NO. : 30), DOM4-29 (SEQ ID NO: 31), DOM4-31 (SEQ ID NO: 32), DOM4-32 (SEQ ID NO: 33), DOM4-33 (SEQ ID NO: 34), DOM4- 34 (SEQ ID NO: 35), DOM4-36 (SEQ ID NO: 36), DOM4-37 (SEQ ID NO: 37), DOM4-38 (SEQ ID NO: 38), DOM4-39 (SEQ ID NO: 39), DOM4 -40 (SEQ ID NO: 40), DOM4-41 (SEQ ID NO: 41), DOM4-42 (SEQ ID NO: 42), DOM4-44 (SEQ ID NO: 43), DOM4-45 (SEQ ID NO. : 44), DOM4-46 (SEQ ID NO: 45), DOM4-49 (SEQ ID NO: 46), DOM4-50 (SEQ ID NO: 47), DOM4-74 (SEQ ID NO.48), DOM4-75 (SEQ ID NO: 49), DOM4-76 (SEQ ID NO: 50), DOM4-78 (SEQ ID NO: 51) ), DOM4-79 (SEQ ID NO: 52), DOM4-80 (SEQ ID NO: 53), DOM4-81 (SEQ ID NO: 54), DOM4-82 (SEQ ID NO: 55), DOM4-83 ( SEQ ID NO: 56), DOM4-84 (SEQ ID NO: 57), DOM4-85 (SEQ ID NO: 58), DOM4-86 (SEQ ID NO: 59), DOM4-87 (SEQ ID NO: 60), DOM4-88 (SEQ ID NO.61), DOM4-89 (SEQ ID NO: 62), DOM4-90 (SEQ ID NO: 63), DOM4-91 (SEQ ID NO.64), DOM4-92 (SEQ ID NO: 65), DOM4-93 (SEQ ID NO: 66), DOM4-94 (SEQ ID NO: 67), DOM4 -95 (SEQ ID NO: 68), DOM4-96 (SEQ ID NO: 69), DOM4-97 (SEQ ID NO: 70), DOM4-98 (SEQ ID NO: 71), DOM4-99 (SEQ ID NO: 72), DOM4-100 (SEQ ID NO: 73), DOM4-101 (SEQ ID NO: 74), DOM4 -102 (SEQ ID NO: 75), DOM4-103 (SEQ ID NO: 76), DOM4-104 (SEQ ID NO: 77), DOM4-105 (SEQ ID NO: 78), DOM4-106 (SEQ ID NO. : 79), DOM4-107 (SEQ ID NO: 80), DOM4-108 (SEQ ID NO: 81), DOM4-109 (SEQ ID NO: 82), DOM4-110 (SEQ ID NO: 83), DOM4-111 (SEQ ID NO: 84), DOM4-112 (SEQ ID NO: 85), DOM4-113 (SEQ ID NO: 86) ), DOM4-114 (SEQ ID NO: 87), DOM4-115 (SEQ ID NO: 88), DOM4-116 (SEQ ID NO: 89), DOM4-117 (SEQ ID NO: 90), DOM4-118 ( SEQ ID NO: 91), DOM4-119 (SEQ ID NO: 92), DOM4-120 (SEQ ID NO.93), DOM4-121 (SEQ ID NO.94), DOM4-123 (SEQ ID NO: 166), DOM4-124 (SEQ ID NO: 167) DOM4-125 (SEQ ID NO: 168), DOM4-126 (SEQ ID NO. : 169), DOM4-127 (SEQ ID NO: 170), DOM4-128 (SEQ ID NO: 171), DOM4-129 (SEQ ID NO: 172), DOM4-129-1 (SEQ ID NO: 173,) DOM4-129-2 (SEQ ID NO: 174), DOM4-129-3 (SEQ ID NO: 175), DOM4-129-4 (SEQ ID NO: 176), DOM4-129-5 (SEQ ID NO: 177) ), DOM4-129-6 (SEQ ID NO 78), DOM4-129-7 (SEQ ID NO: 179), DOM4-129-8 (SEQ ID NO: 180 DOM4-129-9 (SEQ ID NO: 181), DOM4-129-10 (SEQ ID NO: 182 DOM4- 129-11 (SEQ ID NO: 183 DOM4-129-12 (SEQ ID NO: 184 DOM4- 129-13 (SEQ ID NO: 185 DOM4- 129-14 (SEQ ID NO: 186 DOM4- 129-15 (SEQ ID NO: 187 DOM4- 129-16 (SEQ ID NO: 188 DOM4- 129-17 (SEQ ID NO: 189 DOM4-129-18 (SEQ ID NO: 190 DOM4- 129-19 (SEQ ID NO: 191 DOM4- 129 20 (SEQ ID NO: 192 DOM4- 129-21 (SEQ ID NO: 193 DOM4- 129 • 22 (SEQ ID NO: 194 DOM4- 129-23 (SEQ ID NO: 195 DOM4- 129 • 24 (SEQ ID NO: 196 DOM4- 129-25 (SEQ ID NO: 197 DOM4- 129 • 26 (SEQ ID NO: 198 DOM4- 129 27 (SEQ ID NO: 199 DOM4- 129 • 28 (SEQ ID NO: 200 DOM4- 129-29 (SEQ ID NO: 201 DOM4- 129-31 (SEQ ID NO: 202 DOM4 129 -32 (SEQ ID NO: 203 DOM4- 129 -33 (SEQ ID NO.204 DOM4 129 -34 (SEQ ID NO: 205 DOM4 129 -35 (SEQ ID NO: 206 DOM4 -129 -37 (SEQ ID NO: 207 DOM4 -129 -38 (SEQ ID NO: 208 DOM4 -129 -39 (SEQ ID NO: 209 DOM4 -129 -40 (SEQ ID NO: 210 DOM4 -129 -41 (SEQ ID NO: 211 DOM4 -129 -42 (SEQ ID NO: 212 DOM4 -129 -43 (SEQ ID NO: 213 DOM4 -129 -44 (SEQ ID NO: 214 DOM4-131 (SEQ ID NO: 347), DOM4-132 (SEQ ID NO: 348), and DOM4-133 (SEQ ID NO 349) 31 The ligand of claim 30, wherein said monomer of dAb has binding specificity for IL-1R1, and inhibits the binding of IL-1 and IL-1ra with IL-1R1, it comprises an amino acid sequence having an amino acid sequence identity of at least about 90 percent with the amino acid sequence of a dAb selected from the group consisting of DOM4-122-23 (SEQ. ID NO 1), DOM4-122-24 (SEQ ID NO 2), DOM4-122 (SEQ ID NO 95), DOM4-122-1 (SEQ ID NO 96), DOM4-122-2 (SEQ ID NO 97), DOM4-122-3 (SEQ ID NO 98), DOM4-122-4 (SEQ ID NO 99), DOM4-122-5 (SEQ ID NO 100), DOM4-122-6 (SEQ ID NO 101) ), DOM4-122-7 (SEQ ID NO 102), DOM4-122-8 (SEQ ID NO 103), DOM4-122-9 (SEQ ID NO 104), DOM4-122-10 (SEQ ID NO 105), DOM4-122-11 (SEQ ID NO 106), DOM4-122-12 (SEQ ID NO 107), DOM4-122-13 (SEQ ID NO 108), DOM4-122-14 (SEQ ID NO 109), DOM4-122-15 (SEQ ID NO 110), DOM4-122-16 (SEQ ID NO 111), DOM4- 122-17 (SEQ ID NO 112), DOM4-122-18 (SEQ ID NO 113), DOM4-122-19 (SEQ ID NO 114), DOM4-122-20 (SEQ ID NO 115), DOM4-122- 21 (SEQ ID NO 116), DOM4-122-22 (SEQ ID NO 117), DOM4-122-25 (SEQ ID NO 118), DOM4-122-26 (SEQ ID NO 119), DOM4-122-27 (SEQ ID NO 120), DOM4-122-28 (SEQ ID NO 121), DOM4- 122-29 (SEQ ID NO 122), DOM4-122-30 (SEQ ID NO 123), DOM4-122-31 (SEQ ID NO 124), DOM4-122-32 (SEQ ID NO 125), DOM4-122- 33 (SEQ ID NO 126), DOM4-122-34 (SEQ ID NO 127), DOM4- 122-35 SEQ ID NO: 128) DOM4-122-36 (SEQ ID NO: 129) DOM4- 122-37 SEQ ID NO: 130) DOM4-122-38 (SEQ ID NO: 131) DOM4- 122-39 SEQ ID NO: 132) DOM4-122-40 (SEQ ID NO: 133) DOM4-122-41 SEQ ID NO: 134) DOM4-122-42 (SEQ ID NO: 135) DOM4- 122- 43 SEQ ID NO: 136) DOM4-122-44 (SEQ ID NO: 137) DOM4- 122-45 SEQ ID NO: 138) DOM4-122-46 (SEQ ID NO: 139) DOM4- 122 47 SEQ ID NO: 140), DOM4-122-48 (SEQ ID NO-.141) DOM4- 122 -49 SEQ ID NO: 142) DOM4-122-50 (SEQ ID NO: 143) DOM4-122 • 51 SEQ ID NO: 144) DOM4-122-52 (SEQ ID NO: 145) DOM4- 122 -54 SEQ ID NO: 146) DOM4-122-55 (SEQ ID NO: 147) DOM4-122 • 56 SEQ ID NO: 148) DOM4-122-57 (SEQ ID NO: 149) DOM4- 122 -58 SEQ ID NO: 150), DOM4-122-59 (SEQ ID NO-.151) DOM4- 122 -60 SEQ ID NO: 152) DOM4-122-61 (SEQ ID NO: 153) DOM4 122 -62 SEQ ID NO: 154) DOM4-122-63 (SEQ ID NO: 155) DOM4 -122 -64 SEQ ID NO: 156) DOM4-122-65 (SEQ ID NO: 157) DOM4 -122 -66 SEQ ID NO: 158) DOM4-122-67 (SEQ ID NO: 159) DOM4 -122 -68 SEQ ID NO: 160) DOM4-122-69 (SEQ ID NO: 161) DOM4 -122 -70 SEQ ID NO: 162) DOM4-122-71 (SEQ ID NO: 163) DOM4 -122 -72 SEQ ID NO: 164) DOM4-122-73 (SEQ ID NO: 165) DOM4-1 (SEQ ID NO: 8), DOM4-2 (SEQ ID NO: 9), DOM4-3 (SEQ ID NO: 10), DOM4-4 (SEQ ID NO: 11), DOM4-5 (SEQ ID NO: 12), DOM4-6 (SEQ ID NO: 13), DOM4-7 (SEQ ID NO: 14), DOM4-8 (SEQ ID NO: 15), DOM4-9 (SEQ ID NO: 16), DOM4 -10 (SEQ ID NO: 17), DOM4-11 (SEQ ID NO: 18), DOM4-12 (SEQ ID NO: 19), DOM4-13 (SEQ ID NO: 20), DOM4-14 (SEQ ID NO. .21), DOM4-15 (SEQ ID NO: 22), DOM4-20 (SEQ ID NO: 23), DOM4-21 (SEQ ID NO: 24), DOM4-22 (SEQ ID NO: 25), DOM4-23 (SEQ ID NO: 26), DOM4-25 (SEQ ID NO: 27) ), DOM4-26 (SEQ ID NO: 28), DOM4-27 (SEQ ID NO: 29), DOM4-28 (SEQ ID NO: 30), DOM4-29 (SEQ ID NO: 31), DOM4-31 ( SEQ ID NO: 32), DOM4-32 (SEQ ID NO: 33), DOM4-33 (SEQ ID NO: 34), DOM4-34 (SEQ ID NO: 35), DOM4-36 (SEQ ID NO: 36), DOM4-37 (SEQ ID NO: 37), DOM4-38 (SEQ ID NO: 38), DOM4-39 (SEQ ID NO: 39), DOM4-40 (SEQ ID NO: 40), DOM4-41 (SEQ ID NO: 41), DOM4-42 (SEQ ID NO: 42), DOM4-44 (SEQ ID NO: 43), DOM4 -45 (SEQ ID NO: 44), DOM4-46 (SEQ ID NO: 45), DOM4-49 (SEQ ID NO: 46), DOM4-50 (SEQ ID NO: 47), DOM4-74 (SEQ ID NO: 48), DOM4-75 (SEQ ID NO: 49), DOM4-76 (SEQ ID NO: 50), DOM4 -78 (SEQ ID NO: 51), DOM4-79 (SEQ ID NO: 52), DOM4-80 (SEQ ID NO: 53), DOM4-81 (SEQ ID NO: 54), DOM4-82 (SEQ ID NO. : 55), DOM4-83 (SEQ ID NO: 56), DOM4-84 (SEQ ID NO: 57), DOM4-85 (SEQ ID NO: 58), DOM4-86 (SEQ ID NO: 59), DOM4-87 (SEQ ID NO: 60), DOM4-88 (SEQ ID NO: 61), DOM4-89 (SEQ ID NO: 62) ), DOM4-90 (SEQ ID NO: 63), DOM4-91 (SEQ ID NO: 64), DOM4-92 (SEQ ID NO: 65), DOM4-93 (SEQ ID NO: 66), DOM4-94 ( SEQ ID NO: 67), DOM4-95 (SEQ ID NO: 68), DOM4-96 (SEQ ID NO: 69), DOM4-97 (SEQ ID NO: 70), DOM4-98 (SEQ ID NO: 71), DOM4-99 (SEQ ID NO: 72), DOM4-100 (SEQ ID NO: 73), DOM4-101 (SEQ ID NO: 74), DOM4-102 (SEQ ID NO: 75), DOM4-103 (SEQ ID NO: 76), DOM4-104 (SEQ ID NO: 77), DOM4-105 (SEQ ID NO: 78), DOM4 -106 (SEQ ID NO: 79), DOM4-107 (SEQ ID NO: 80), DOM4-108 (SEQ ID NO: 81), DOM4-109 (SEQ ID NO: 82), DOM4-110 (SEQ ID NO: 83), DOM4-111 (SEQ ID NO: 84), DOM4-112 (SEQ ID NO: 85), DOM4 -113 (SEQ ID NO: 86), DOM4-114 (SEQ ID NO: 87), DOM4-115 (SEQ ID NO: 88), DOM4-116 (SEQ ID NO: 89), DOM4-117 (SEQ ID NO. : 90), DOM4-118 (SEQ ID NO: 91), DOM4-119 (SEQ ID NO: 92), DOM4-120 (SEQ ID NO: 93), DOM4-121 (SEQ ID NO: 94), DOM4- 123 (SEQ ID NO: 166), DOM4-124 (SEQ ID NO: 167) DOM4-125 (SEQ ID NO: 168), DOM4-126 (SEQ ID NO: 169), DOM4-127 (SEQ ID NO: 170) ), DOM4-128 (SEQ ID NO: 171), DOM4-129 (SEQ ID NO: 172), DOM4-129-1 (SEQ ID NO-.173,) DOM4-129-2 (SEQ ID NO: 174) , DOM4-129-3 (SEQ ID NO: 175), DOM4-129-4 (SEQ ID NO: 176), DOM4-129-5 (SEQ ID NO: 177), DOM4-129-6 (SEQ ID NO- .178), DOM4-129-7 (SEQ ID NO: 179) DOM4-129-8 (SEQ ID NO: 180 DOM4-129-9 (SEQ ID NO: 181) DOM4-129-10 (SEQ ID NO: 182 DOM4-129-11 (SEQ ID NO: 183) DOM4-129-12 (SEQ ID NO: 184 DOM4-129-13 (SEQ ID NO: 185) DOM4-129-14 (SEQ ID NO: 186 DOM4-129-15 (SEQ ID NO: 187) DOM4-129- 16 (SEQ ID NO: 188 DOM4-129-17 (SEQ ID NO: 189) DOM4-129-18 (SEQ ID NO: 190 DOM4-129-19 (SEQ ID NO: 191) DOM4-129-20 (SEQ ID NO: 192 DOM4-129-21 (SEQ ID NO: 193) DOM4-129-22 (SEQ ID NO: 194 DOM4-129-23 (SEQ ID NO: 195) DOM4-129-24 (SEQ ID NO: 196 DOM4 -129-25 (SEQ ID NO: 197) DOM4-129-26 (SEQ ID NO: 198 DOM4-129-27 (SEQ ID NO: 199) DOM4-129-28 (SEQ ID NO: 200) DOM4-129-29 (SEQ ID NO: 201) DOM4-129-31 (SEQ ID NO: 202 DOM4-129-32 (SEQ ID NO: 203) DOM4-129-33 (SEQ ID NO: 204 DOM4-129-34 (SEQ ID NO: 205), DOM4-129-35 (SEQ ID NO: 206), DOM4-129-37 (SEQ ID NO: 207), DOM4-129-38 (SEQ ID NO: 208), DOM4-129-39 ( SEQ ID NO: 209), DOM4-129-40 (SEQ ID NO: 210), DOM4-129-41 (SEQ ID NO: 211), DOM4-129-42 (SEQ ID NO: 212), DOM4-129- 43 (SEQ ID NO: 213), DOM4-129-44 (SEQ ID NO: 214), DOM4-131 (SEQ ID NO: 347), DOM4-132 (SEQ ID NO-.348), and DOM4-133 (SEQ ID NO: 349). 32. The ligand of any of claims 29 to 31, wherein said dAb monomer has binding specificity for TNFR1, and competes for binding to TNFR1 with a dAb selected from the group consisting of TAR2h-12 (SEQ ID NO: 785), TAR2h-13 ( SEQ ID NO: 786), TAR2h-14 (SEQ ID NO: 787), TAR2h-16 (SEQ ID NO: 788), TAR2h-17 (SEQ ID NO: 789), TAR2h-18 (SEQ ID NO: 790) , TAR2h-19 (SEQ ID NO: 791), TAR2h-20 (SEQ ID NO: 792), TAR2h-21 (SEQ ID NO: 793), TAR2h-22 (SEQ ID NO: 794), TAR2h-23 (SEQ ID NO: 795), TAR2h-24 (SEQ ID NO: 796), TAR2h-25 (SEQ ID NO: 797), TAR2h-26 (SEQ ID NO: 798), TAR2h -27 (SEQ ID NO: 799), TAR2h-29 (SEQ ID NO: 800), TAR2h-30 (SEQ ID NO: 801), TAR2h-32 (SEQ ID NO: 802), TAR2h-33 (SEQ ID NO : 803), TAR2h-10-1 (SEQ ID NO: 804), TAR2h-10-2 (SEQ ID NO: 805), TAR2h-10-3 (SEQ ID NO: 806), TAR2h-10-4 (SEQ ID NO: 807), TAR2h-10-5 (SEQ ID NO: 808), TAR2h-10-6 (SEQ ID NO: 809 ), TAR2h-10-7 (SEQ ID NO: 810), TAR2h-10-8 (SEQ ID NO: 811), TAR2h-10-9 (SEQ ID NO: 812), TAR2h-10-10 (SEQ ID NO : 813), TAR2h-10-11 l (SEQ ID NO: 814), TAR2h-10-12 (SEQ ID NO: 815), TAR2h-10-13 (SEQ ID NO: 816), TAR2h-10-14 (SEQ ID NO: 817), TAR2h- 10-15 SEQ ID NO: 818 TAR2h-10-16 (SEQ ID NO 819), TAR2h- 10-17 SEQ ID NO: 820 TAR2h-10-18 (SEQ ID NO 821), TAR2h- 10-19 SEQ ID NO: 822 TAR2h-10-20 (SEQ ID NO 823), TAR2h- 10-21 SEQ ID NO: 824 TAR2h-10-22 (SEQ ID NO: 825), TAR2h- 10-27 SEQ ID NO: 826 TAR2h-10-29 (SEQ ID NO 827), TAR2h- 10-31 SEQ ID NO: 828 TAR2h-10-35 (SEQ ID NO 829), TAR2h- 10-36 SEQ ID NO: 830 TAR2h-10-37 (SEQ ID NO 831), TAR2h- 10-38 SEQ ID NO: 832 TAR2h-10-45 (SEQ ID NO: 833), TAR2h- 10-47 SEQ ID NO: 834 TAR2h-10-48 (SEQ ID NO 835), TAR2h- 10-57 SEQ ID NO: 836, TAR2h-10-56 SEQ ID NO 837), TAR2h- 10-58 SEQ ID NO: 838 TAR2h-10-66 (SEQ ID NO: 839), TAR2h- 10-64 SEQ ID NO: 840 TAR2h-10-65 (SEQ ID NO: 841) TAR2h- 10-68 SEQ ID NO: 842 TAR2h-10-69 (SEQ ID NO 843) TAR2h- 10-67 (SEQ ID NO: 844, TAR2h-10-61 (SEQ ID NO 845) TAR2h- 10-62 SEQ ID NO: 846 TAR2h-10-63 (SEQ ID NO: 847) TAR2h- 10-60 SEQ ID NO: 848 TAR2h-10-55 (SEQ ID NO: 849) TAR2h- 10-59 SEQ ID NO: 850) TAR2h-10-70 (SEQ ID NO: 851), TAR2h-34 (SEQ ID NO: 852), TAR2h-35 (SEQ ID NO: 853), TAR2h-36 (SEQ ID NO: 854), TAR2h-37 (SEQ ID NO: 855), TAR2h-38 (SEQ ID NO: 856), TAR2h-39 (SEQ ID NO: 857), TAR2h-40 (SEQ ID NO: 858), TAR2h-41 (SEQ ID NO: 859), TAR2h-42 (SEQ ID NO: 860), TAR2h-43 (SEQ ID NO: 861), TAR2h-44 (SEQ ID NO: 862), TAR2h -45 (SEQ ID NO: 863), TAR2h-47 (SEQ ID NO: 864), TAR2h-48 (SEQ ID NO: 865), TAR2h-50 (SEQ ID NO: 866), TAR2h-51 (SEQ ID NO : 867), TAR2h-66 (SEQ ID NO: 868), TAR2h-67 (SEQ ID NO: 869), TAR2h-68 (SEQ ID NO: 870), TAR2h-70 (SEQ ID NO: 871), TAR2h-71 (SEQ ID NO: 872), TAR2h-72 (SEQ ID NO: 873), TAR2h-73 (SEQ ID NO: 874), TAR2h-74 (SEQ ID NO: 875), TAR2h-75 (SEQ ID NO: 876), TAR2h -76 (SEQ ID NO: 877), TAR2h-77 (SEQ ID NO: 878), TAR2h-78 (SEQ ID NO: 879), TAR2h-79 (SEQ ID NO: 880), TAR2h-15 (SEQ ID NO: 881), TAR2h-131-8 (SEQ ID NO: 882), TAR2h-131-24 (SEQ ID NO: 883), TAR2h-15-8 (SEQ ID NO: 884), TAR2h-15-8-1 (SEQ ID NO: 885), TAR2h-15-8-2 (SEQ ID NO: 886), TAR2h-185- 23 (SEQ ID NO: 887), TAR2h-154-10-5 (SEQ ID NO: 888), TAR2h-14-2 (SEQ ID NO: 889), TAR2h-151-8 (SEQ ID NO: 890), TAR2h-152-7 (SEQ ID NO: 891), TAR2h-35-4 (SEQ ID NO: 892), TAR2h-154-7 (SEQ ID NO: 893) ), TAR2h-80 (SEQ ID NO: 894), TAR2h-81 (SEQ ID NO: 895), TAR2h-82 (SEQ ID NO: 896), TAR2h-83 (SEQ ID NO: 897), TAR2h-84 ( SEQ ID NO: 898), TAR2h-85 (SEQ ID NO: 899), TAR2h-86 (SEQ ID NO: 900), TAR2h-87 (SEQ ID NO: 901), TAR2h-88 (SEQ ID NO: 902), TAR2h-89 (SEQ ID NO: 903), TAR2h-90 (SEQ ID NO: 904), TAR2h-91 (SEQ ID NO: 905), TAR2h-92 (SEQ ID NO: 906), TAR2h-93 (SEQ ID NO: 907), TAR2h-94 (SEQ ID NO: 908), TAR2h-95 (SEQ ID NO: 909), TAR2h -96 (SEQ ID NO: 910), TAR2h-97 (SEQ ID NO: 911), TAR2h-99 (SEQ ID NO: 912), TAR2h-100 (SEQ ID NO: 913), TAR2h-101 (SEQ ID NO: 914), TAR2h-102 (SEQ ID NO: 915), TAR2h-103 (SEQ ID NO: 916), TAR2h -104 (SEQ ID NO: 917), TAR2h-105 (SEQ ID NO: 918), TAR2h-106 (SEQ ID NO: 919), TAR2h-107 (SEQ ID NO: 920), TAR2h-108 (SEQ ID NO. : 921), TAR2h-109 (SEQ ID TAR2h-110 (SEQ ID NO: 923 TAR2h-111 (SEQ ID TAR2h-112 (SEQ ID NO: 925 TAR2h-113 (SEQ ID TAR2h-114 (SEQ ID NO: 927 TAR2h-115 (SEQ ID TAR2h-116 (SEQ ID NO: 929 TAR2h-117 (SEQ ID TAR2h-118 (SEQ ID NO: 931 TAR2h-119 (SEQ ID TAR2h-120 (SEQ ID NO: 933 TAR2h-121 (SEQ ID TAR2h-122 (SEQ ID NO: 935 TAR2h-123 (SEQ ID TAR2h-124 (SEQ ID NO: 937 TAR2h-125 (SEQ ID TAR2h-l26 (SEQ ID NO: 939 TAR2h-127 (SEQ ID TAR2h-128 (SEQ ID NO: 941 TAR2h-129 (SEQ ID TAR2h-130 (SEQ ID NO: 943 TAR2h-131 (SEQ ID TAR2h-132 (SEQ ID NO: 945 TAR2h-133 (SEQ ID TAR2h-151 (SEQ ID NO: 947 TAR2h-152 (SEQ ID TAR2h-153 (SEQ ID NO: 949 TAR2h-154 (SEQ ID TAR2h-159 (SEQ ID NO: 951 TAR2h-165 (SEQ ID TAR2h-166 (SEQ ID NO: 953 TAR2h-168 (SEQ ID TAR2h-171 (SEQ ID NO: 955 TAR2h-172 (SEQ ID TAR2h-173 (SEQ ID NO: 957 TAR2h-174 (SEQ ID TAR2h-176 (SEQ ID NO: 959 TAR2h-178 (SEQ ID TAR2h-201 (SEQ ID NO: 961 TAR2h-202 (SEQ ID TAR2h-203 (SEQ ID NO: 963 TAR2h-204 (SEQ ID TAR2h-185-25 (SEQ ID NO: 965 TAR2h-154-10 SEQ ID TAR2h-205 (SEQ ID NO: 967), TA R2h-10 (SEQ ID NO: 968), TAR2h-5 (SEQ ID NO: 969), TAR2h-5d1 (SE Q ID NO: 970), TAR2h-5d2 (SEQ ID NO: 971), TAR2h-5d3 (SEQ ID NO: 972), TAR2h-5d4 (SEQ ID NO 973) TAR2h-5d5 (SEQ ID NO 974), TAR2h-5d6 (SEQ ID NO 975), TAR2h-5d7 (SEQ ID NO 976), TAR2h-5d8 (SEQ ID NO 977), TAR2h-5d9 (SEQ ID NO 978), TAR2h-5d10 (SEQ ID NO 979), TAR2h-5d11 (SEQ ID NO 980), TAR2h-5d12 (SEQ ID NO 981), and TAR2h-5d13 (SEQ ID NO 982) 33 The ligand of claim 32, wherein said dAb monomer has binding specificity for TNFR1, and comprises a sequence of amino acids having an amino acid sequence identity of at least about 90 percent with the amino acid sequence of a dAb selected from the group consisting of TAR2h-12 (SEQ ID NO 785), TAR2h-13 (SEQ ID NO 786), TAR2h-14 (SEQ ID No. 787), TAR2h-16 (SEQ ID No. 788), TAR2h-17 (SEQ ID No. 789), TAR2h-18 (SEQ ID No. 790), TAR2h-19 (SEQ ID NO 791), TAR2h-20 (SEQ ID No. 792), TAR2h-21 (SEQ ID No. 793), TAR2h-22 (SEQ ID NO 794), TAR2h-23 (SEQ ID No. 795), TAR2h-24 (SEQ ID No. 796), TAR2h-25 (SEQ ID No. 797), TAR2h-26 (SEQ ID No. 798), TAR2h-27 (SEQ ID NO 799), TAR2h-29 (SEQ ID NO 800), TAR2h-30 (SEQ ID NO 801), TAR2h-32 (SEQ ID NO 802), TAR2h-33 (SEQ ID NO 803), TAR2h-10-l ( SEQ ID NO 804), TAR2h-10-2 (SEQ ID NO 805), TAR2h- 10-3 (SEQ ID NO 806), TAR2h-10-4 (SEQ ID NO 807), TAR2h-10-5 (SEQ ID NO 808), TAR2h-10-6 (SEQ ID NO 809), TAR2h-10-7 (SEQ ID NO 810), TAR2h-10-8 (SEQ ID NO 81 I), TAR2h-10-9 (SEQ ID NO 812), TAR2h-10-10 (SEQ ID NO 813), TAR2h-10-l I (SEQ ID NO 814), TAR2h-10-12 (SEQ ID NO 815), TAR2h-10-13 (SEQ ID NO: 816), TAR2h-10-14 (SEQ ID NO: 817), TAR2h-10-15 (SEQ ID NO: 818), TAR2h-10-16 (SEQ ID NO: 819), TAR2h-10-17 ( SEQ ID NO: 820), TAR2h-10-18 (SEQ ID NO: 821), TAR2h-10-19 (SEQ ID NO: 822), TAR2h-10-20 (SEQ ID NO: 823), TAR2h-10- 21 (SEQ ID NO: 824), TAR2h-10-22 (SEQ ID NO: 825), TAR2h-10-27 (SEQ ID NO: 826), TAR2h-10-29 (SEQ ID NO: 827), TAR2h-10-31 (SEQ ID NO: 828), TAR2h-10-35 (SEQ ID NO: 829), TAR2h-10-36 ( SEQ ID NO: 830), TAR2h-10-37 (SEQ ID NO: 831), TAR2h-10-38 (SEQ ID NO: 832), TAR2h-10-45 (SEQ ID NO: 833), TAR2h-10- 47 (SEQ ID NO: 834), TAR2h-10-48 (SEQ ID NO: 835), TAR2h-10-57 (SEQ ID NO: 836), TAR2h-10-56 SEQ ID NO: 837), TAR2h-10-58 (SEQ ID NO: 838), TAR2h-10-66 (SEQ ID NO: 839), TAR2h-10-64 (SEQ ID NO: 840), TAR2h-10-65 (SEQ ID NO: 841), TAR2h-10-68 (SEQ ID NO: 842), TAR2h-10-69 (SEQ ID NO: 843), TAR2h-10-67 (SEQ ID NO: 844), TAR2h-10-61 (SEQ ID NO: 845), TAR2h-10-62 (SEQ ID NO: 846), TAR2h-10-63 (SEQ ID NO: 847), TAR2h-10-60 (SEQ ID NO: 848), TAR2h-10-55 (SEQ ID NO: 849), TAR2h-10-59 ( SEQ ID NO: 850), TAR2h-10-70 (SEQ ID NO: 851), TAR2h-34 (SEQ ID NO: 852), TAR2h-35 (SEQ ID NO: 853), TAR2h-36 (SEQ ID NO: 854), TAR2h-37 (SEQ ID NO: 855), TAR2h-38 (SEQ ID NO: 856), TAR2h-39 (SEQ ID NO: 857), TAR2h-40 (SEQ ID NO: 858), TAR2h-41 (SEQ ID NO: 859), TAR2h-42 (SEQ ID NO: 860), TAR2h-43 (SEQ ID NO: 861) ), TAR2h-44 (SEQ ID NO: 862), TAR2h-45 (SEQ ID NO: 863), TAR2h-47 (SEQ ID NO: 864), TAR2h-48 (SEQ ID NO: 865), TAR2h-50 ( SEQ ID NO: 866), TAR2h-51 (SEQ ID NO: 867), TAR2h-66 (SEQ ID NO: 868), 22] TAR2h-67 (SEQ ID NO: 869), TAR2h-68 (SEQ ID NO: 870), TAR2h-70 (SEQ ID NO: 871), TAR2h-71 (SEQ ID NO: 872), TAR2h-72 (SEQ ID NO: 873), TAR2h-73 (SEQ ID NO: 874), TAR2h-74 (SEQ ID NO: 875), TAR2h-75 (SEQ ID NO: 876), TAR2h-76 (SEQ ID NO: 877), TAR2h -77 (SEQ ID NO: 878), TAR2h-78 (SEQ ID NO: 879), TAR2h-79 (SEQ ID NO: 880), TAR2h-15 (SEQ ID NO: 881), TAR2h-131-8 (SEQ ID NO: 882), TAR2h-131-24 (SEQ ID NO: 883), TAR2h-15-8 (SEQ ID NO: 884), TAR2h-15-8-l (SEQ ID NO: 885), TAR2h-15-8-2 (SEQ ID NO: 886), TAR2h-185-23 (SEQ ID NO: 887), TAR2h- 154-10-5 (SEQ ID NO: 888), TAR2h-14-2 (SEQ ID NO: 889), TAR2h-151-8 (SEQ ID NO: 890), TAR2h-152-7 (SEQ ID NO: 891), TAR2h-35-4 (SEQ ID NO: 892), TAR2h-154-7 (SEQ ID NO: 893), TAR2h-80 (SEQ ID NO: 894), TAR2h-81 (SEQ ID NO: 895), TAR2h-82 (SEQ ID NO: 896), TAR2h-83 (SEQ ID NO: 897), TAR2h-84 (SEQ ID NO: 898), TAR2h -85 (SEQ ID NO: 899), TAR2h-86 (SEQ ID NO: 900), TAR2h-87 (SEQ ID NO: 901), TAR2h-88 (SEQ ID NO: 902), TAR2h-89 (SEQ ID NO: 903), TAR2h-90 (SEQ ID NO: 904), TAR2h-91 (SEQ ID NO: 905), TAR2h -92 (SEQ ID NO: 906), TAR2h-93 (SEQ ID NO: 907), TAR2h-94 (SEQ ID NO: 908), TAR2h-95 (SEQ ID NO: 909), TAR2h-96 (SEQ ID NO : 910), TAR2h-97 (SEQ ID NO: 911), TAR2h-99 (SEQ ID NO: 912), TAR2h-100 (SEQ ID NO: 913), TAR2h-101 (SEQ ID NO: 914), TAR2h-102 (SEQ ID NO: 915), TAR2h-103 (SEQ ID NO: 916), TAR2h-104 (SEQ ID NO: 917) ), TAR2h-105 (SEQ ID NO: 918), TAR2h-106 (SEQ ID NO: 919), TAR2h-107 (SEQ ID NO: 920), TAR2h-108 (SEQ ID NO: 921), TAR2h-109 ( SEQ ID NO: 922), TAR2h-110 (SEQ ID NO: 923), TAR2h-111 SEQ ID NO: 924) TAR2h-112 SEQ ID NO: 925), TAR2h-113 SEQ ID NO: 926) TAR2h-114 SEQ ID NO 927), TAR2h-115 SEQ ID NO: 928) TAR2h-116 SEQ ID NO: 929), TAR2h-117 SEQ ID NO: 930) TAR2h-118 SEQ ID NO: 931), TAR2h-119 SEQ ID NO: 932) TAR2h-120 SEQ ID NO 933), TAR2h-121 SEQ ID NO: 934) TAR2h-122 SEQ ID NO 935), TAR2h-123 SEQ ID NO: 936) TAR2h-124 SEQ ID NO 937), TAR2h-125 SEQ ID NO: 938) TAR2h-126 SEQ ID NO 939), TAR2h-127 SEQ ID NO: 940) TAR2h-128 SEQ ID N NOO: 9 94411)) ,, TAR2h-129 SEQ ID NO: 942) TAR2h-130 SEQ ID NO 943), TAR2h-131 SEQ ID NO: 944) TAR2h-132 SEQ ID NO 945), TAR2h-133 SEQ ID NO: 946) TAR2h-151 SEQ ID NO 947), TAR2h-152 SEQ ID NO: 948) TAR2h-153 SEQ ID NO: 949), TAR2h-154 SEQ ID NO: 950) TAR2h-159 SEQ ID N NOO: 9 95511)) ,, TAR2h-165 SEQ ID NO: 952) TAR2h-166 SEQ ID NO: 953), TAR2h-168 SEQ ID NO: 954) TAR2h-171 SEQ ID NO: 955), TAR2h-172 SEQ ID NO: 956) TAR2h-173 SEQ ID NO 957), TAR2h-174 SEQ ID NO: 958) TAR2h-176 SEQ ID NO 959), TAR2h-178 SEQ ID NO: 960) TAR2h-201 SEQ ID N NOO:: 996611)) ,, TAR2h-202 SEQ ID NO: 962) TAR2h-203 SEQ ID NO: 963) TAR2h-204 (SEQ ID NO: 964), TAR2h-185-25 (SEQ ID NO: 965) TAR2h-154-10 (SEQ ID NO: 966), TAR2h-205 (SEQ ID NO: 967) TAR2h-10 (SEQ ID NO: 968), TAR2h-5 (SEQ ID NO: 969), TAR2h-5d1 (SEQ ID NO: 970), TAR2h-5d2 (SEQ ID NO: 971), TAR2h- 5d3 (SEQ ID NO: 972), TAR2h-5d4 (SEQ ID NO: 973), TAR2h-5d5 (SEQ ID NO 974), TAR2h-5d6 (SEQ ID NO 975), TAR2h-5d7 (SEQ ID NO 976), TAR2h-5d8 (SEQ ID NO 977), TAR2h-5d9 (SEQ ID NO 978), TAR2h-5d10 (SEQ ID NO 979), TAR2h-5d11 (SEQ ID NO 980), TAR2h-5d12 (SEQ ID NO 981), and TAR2h-5d13 (SEQ ID NO 982) 34 The ligand of any of claims 29 to 33, which further comprises a fraction that prolongs the half-life of the ligand of claim 34, wherein the fraction that prolongs the aforementioned half-life is a polyalkylene glycol fraction, serum albumin or a fragment thereof, a transferpna receptor or a linkpna binding portion thereof, or an antibody or antibody fragment comprising a linker site for a polypeptide that improves the half-life m vivo 36 The ligand of claim 35, wherein the fraction that prolongs the half-life mentioned is a polyalkylene glycol fraction 37 The ligand of claim 35, wherein the fraction that prolongs the aforementioned life is a antibody or an antibody fragment comprising a binding site for serum albumin or for the neonatal Fe receptor 38 The ligand of claim 37, wherein said antibody or antibody fragment is an antibody fragment, and this fragment of antibody is a single immunoglobulin variable domain 39. The ligand of claim 38, wherein the only immunoglobulin variable domain mentioned competes for binding to human serum albumin, with a dAb selected from the group consisting of DOM7m-16 (SEQ ID NO: 723), DOM7m -12 (SEQ ID NO: 724), DOM7m-26 (SEQ ID NO: 725), DOM7r-1 (SEQ ID NO: 726), DOM7r-3 (SEQ ID NO: 727), DOM7r-4 (SEQ ID NO. : 728), DOM7r-5 (SEQ ID NO: 729), DOM7r-7 (SEQ ID NO: 730), DOM7r-8 (SEQ ID NO: 731), DOM7h-2 (SEQ ID NO: 732), DOM7h- 3 (SEQ ID NO: 733), DOM7h-4 (SEQ ID NO: 734), DOM7h-6 (SEQ ID NO: 735), DOM7h-1 (SEQ ID NO: 736), DOM7h-7 (SEQ ID NO: 737), DOM7h-8 (SEQ ID NO: 746), DOM7r-13 (SEQ ID NO: 747), DOM7r-14 (SEQ ID NO: 748), DOM7h-22 (SEQ ID NO: 739), DOM7h-23 (SEQ ID NO: 740), DOM7h-24 (SEQ ID NO: 741), DOM7h-25 (SEQ ID NO: 742), DOM7h-26 (SEQ ID NO: 743), DOM7h-21 (SEQ ID NO: 744), DOM7h -27 (SEQ ID NO: 745), DOM7r-15 (SEQ ID NO: 749), DOM7r-16 (SEQ. ID NO: 750), DOM7r-17 (SEQ ID NO: 751), DOM7r-18 (SEQ ID NO: 752), DOM7r-19 (SEQ ID NO: 753), DOM7r-20 (SEQ ID NO: 754), DOM7r-21 (SEQ ID NO: 755), DOM7r-22 (SEQ ID NO: 756), DOM7r-23 (SEQ ID NO: 757), DOM7r-24 (SEQ ID NO: 758), DOM7r-25 (SEQ ID NO: 759), DOM7r-26 (SEQ ID NO: 760), DOM7r-27 (SEQ ID NO: 761), DOM7r-28 (SEQ ID NO: 762), DOM7r-29 (SEQ ID NO: 763), DOM7r-30 (SEQ ID NO: 764), DOM7r-31 (SEQ ID NO: 765), DOM7r-32 (SEQ ID NO: 766), and DOM7r-33 (SEQ ID NO: 767). 40. The ligand of claim 39, wherein the single immunoglobulin variable domain mentioned binds to the human serum albumin, and comprises an amino acid sequence having an amino acid sequence identity of at least 90 percent, with the amino acid sequence of a dAb selected from the group consisting of DOM7m-16 (SEQ ID NO : 723), DOM7m-12 (SEQ ID NO: 724), DOM7m-26 (SEQ ID NO: 725), DOM7r-1 (SEQ ID NO: 726), DOM7r-3 (SEQ ID NO: 727), DOM7r-4 (SEQ ID NO: 728), DOM7r-5 (SEQ ID NO: 729), DOM7r-7 (SEQ ID NO: 730), DOM7r-8 (SEQ ID NO: 731), DOM7h-2 (SEQ ID NO: 732), DOM7h-3 (SEQ ID NO: 733), DOM7h-4 (SEQ ID NO: 734), DOM7h-6 (SEQ ID NO: 735), DOM7h-1 (SEQ ID NO: 736), DOM7h-7 (SEQ ID NO: 737), DOM7h-8 (SEQ ID NO: 746), DOM7r-13 (SEQ ID NO: 747), DOM7r-14 (SEQ ID NO: 748), DOM7h-22 (SEQ ID NO: 739) ), DOM7h-23 (SEQ ID NO: 740), DOM7h-24 (SEQ ID NO: 741), DOM7h-25 (SEQ ID NO: 742), DOM7h-26 (SEQ ID NO: 743), DOM7h-21 ( SEQ ID NO: 744), DOM7h-27 (SEQ ID NO: 745), DOM7r-15 (SEQ ID NO: 749), DOM7r-16 (SEQ ID NO: 750), DOM7r-17 (SEQ ID NO: 751), DOM7r-18 (SEQ ID NO: 752), DOM7r-19 (SEQ ID NO: 753), DOM7r -20 (SEQ ID NO: 754), DOM7r-21 (SEQ ID NO: 755), DOM7r-22 (SEQ ID NO: 756), DOM7r-23 (SEQ ID NO: 757), DOM7r-24 (SEQ ID NO. : 758), DOM7r-25 (SEQ ID NO: 759), DOM7r-26 (SEQ ID NO: 760), DOM7r-27 (SEQ ID NO: 761), DOM7r-28 (SEQ ID NO: 762), DOM7r-29 (SEQ ID NO: 763), DOM7r-30 (SEQ ID NO: 764), DOM7r-31 (SEQ ID NO: 765) ), DOM7r-32 (SEQ ID NO: 766), and DOM7r-33 (SEQ ID NO: 767). 41. An isolated nucleic acid encoding a dAb monomer or ligand of any of claims 1 to 40. A recombinant nucleic acid encoding a dAb monomer or ligand of any one of claims 1 to 40. A vector comprising a nucleic acid encoding a dAb or ligand monomer of any of claims 1 to 40. The vector of claim 43, wherein this vector is an expression vector. A host cell, which comprises a recombinant nucleic acid of claim 42. A host cell, which comprises a vector of claim 43 or 44. A method for producing a monomer of dAb or a ligand that has a binding specificity for IL-1R1, and inhibits the binding of IL-1 to the receptor, but does not inhibit the binding of IL-1ra to IL-1R1, which comprises maintaining a host cell of claim 45 under conditions suitable for the expression of the aforementioned recombinant nucleic acid. A method for producing a dAb monomer or a ligand having specificity of linkage for IL-1R1, and which inhibits the binding of IL-1 to the receptor, but which does not inhibit the binding of I L-1 ra with IL-1R1, which comprises maintaining a host cell of claim 46 under suitable conditions for the expression of the mentioned vector 49 A pharmaceutical composition, which comprises a dAb monomer or a ligand of any one of claims 1 to 40, and a physiologically acceptable carrier. The pharmaceutical composition of claim 49, wherein this composition is for intravenous, intramuscular, intrapeptoneal, intra-artepal administration, for intrathecal delivery device, intra-articular, or subcutaneous administration 51 The pharmaceutical composition of claim 49, wherein this composition is for pulmonary administration, by intranasal, vaginal, or rectal delivery device 52 A drug delivery device, which comprises the pharmaceutical composition of claim 49. The drug delivery device of claim 52, wherein said drug delivery device is selected from the group consisting of a parenteral delivery device, an intravenous delivery device, an intramuscular delivery device. , an intrapeptoneal delivery device, a transdermal delivery device, a pulmonary delivery device, a mtra-artepal delivery device, an intrathecal delivery device, a articulatory delivery device, a subcutaneous delivery device, a delivery device, intranasal delivery, a device or vaginal delivery, and rectal delivery device 54 The drug delivery device of claim 52, wherein this device is selected from the group consisting of a syringe, a delivery device transdermal, a capsule, a tablet, a nebulizer, an inhaler, an atomizer, an aerosolizer, a fine mist nebulizer, a dry powder inhaler, a metered dose inhaler, a metered dose sprayer, a metered dose nebulizer, a metered dose sprayer, and a catheter. 55. A method for the treatment of an inflammatory disease, which comprises administering to a subject in need thereof, a therapeutically effective amount of a dAb monomer or a ligand of any of claims 1 to 40. 56. The method of Claim 55, wherein the inflammatory disease mentioned is arthritis. 57. A domain antibody monomer (dAb) that is resistant to degradation by the protease, for use in therapy, diagnosis, and / or prophylaxis. 58. The use of a domain antibody monomer (dAb), which is resistant to degradation by the protease, for the manufacture of a medicament for the treatment of an inflammatory disease, arthritis, or a respiratory disease. 59. The use of a domain antibody monomer (dAb), which is resistant to degradation by the protease, for the manufacture of a medicament for pulmonary administration. 60. A method for the treatment of an inflammatory disease, arthritis, or respiratory disease, which comprises administering to a subject in need thereof, a therapeutically effective amount of a monomer antibody domain. (dAb) which is resistant to degradation by the protease. 61. The method of claim 60, wherein the dAb is administered by pulmonary administration. 62. The dAb monomer, the use, or method of any of claims 57 to 61, wherein the dAb monomer is resistant to elastase. 63. The dAb monomer, use, or method of any of claims 57 to 62, wherein the dAb monomer is an immunoglobulin light chain variable domain. 64. The dAb monomer, use, or method of claim 63, wherein the dAb monomer is VK. 65. The dAb monomer, use, or method of any of claims 57 to 64, wherein the dAb has binding specificity for the interleukin-1 type 1 receptor (IL-1R1). 66. The dAb monomer, use, or method of claim 65, wherein the dAb monomer competes for the linkage with IL-1R1, with an anti-L-1 R 1 dAb, wherein this dAb anti- L-1 R 1 consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 349. 67. The dAb monomer, use, or method of claim 66, wherein the dAb monomer competes for the linkage with IL-1R1, with an anti-l L-1 R1 dAb, wherein this dAb anti-l L-1 R 1 consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 1 or SEQ ID NO: 2.
MXMX/A/2008/006882A 2005-12-01 2008-05-28 Noncompetitive domain antibody formats that bind interleukin 1 receptor type 1 MX2008006882A (en)

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