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WO1993012227A1 - Animaux transgeniques non humains capables de produire des anticorps heterologues - Google Patents

Animaux transgeniques non humains capables de produire des anticorps heterologues Download PDF

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Publication number
WO1993012227A1
WO1993012227A1 PCT/US1992/010983 US9210983W WO9312227A1 WO 1993012227 A1 WO1993012227 A1 WO 1993012227A1 US 9210983 W US9210983 W US 9210983W WO 9312227 A1 WO9312227 A1 WO 9312227A1
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Prior art keywords
human
transgene
gene
transgenic
animal
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PCT/US1992/010983
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Inventor
Nils Lonberg
Robert M. Kay
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Genpharm International Inc
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Genpharm International Inc
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Priority claimed from US07/810,279 external-priority patent/US5569825A/en
Priority claimed from US07/853,408 external-priority patent/US5789650A/en
Application filed by Genpharm International Inc filed Critical Genpharm International Inc
Priority to JP5511191A priority Critical patent/JPH07503132A/ja
Priority to EP93901143A priority patent/EP0746609A4/fr
Priority to CA002124967A priority patent/CA2124967C/fr
Priority to US08/053,131 priority patent/US5661016A/en
Publication of WO1993012227A1 publication Critical patent/WO1993012227A1/fr
Anticipated expiration legal-status Critical
Priority to US08/544,404 priority patent/US5770429A/en
Priority to US11/009,840 priority patent/US20060015949A1/en
Priority to US11/009,873 priority patent/US7501552B2/en
Priority to US11/009,769 priority patent/US20060026703A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0276—Knock-out vertebrates
    • A—HUMAN NECESSITIES
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3007—Carcino-embryonic Antigens
    • C—CHEMISTRY; METALLURGY
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    • C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
    • C07K16/4291—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig against IgE
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    • C07—ORGANIC CHEMISTRY
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    • C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/90—Stable introduction of foreign DNA into chromosome
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
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    • A—HUMAN NECESSITIES
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    • A01K2217/00—Genetically modified animals
    • A—HUMAN NECESSITIES
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    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
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    • A01K2267/00—Animals characterised by purpose
    • A01K2267/01—Animal expressing industrially exogenous proteins
    • A—HUMAN NECESSITIES
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    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0381—Animal model for diseases of the hematopoietic system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the invention relates to transgenic non-human animals capable of producing heterologous antibodies
  • transgenic animals used to produce such transgenic animals
  • transgenes capable of functionally rearranging a heterologous D gene in V-D-J recombination, immortalized B-cells capable of producing heterologous antibodies, methods and transgenes for producing heterologous antibodies of multiple isotypes, methods and transgenes for inactivating or suppressing
  • variable region sequence comprises somatic mutation
  • transgenic nonhuman animals which produce antibodies having a human primary sequence and which bind to human antigens.
  • human immunoglobulins that are reactive with specific human antigens that are promising therapeutic and/or diagnostic targets.
  • producing human immunoglobulins that bind specifically with human antigens is problematic.
  • the present technology for generating monoclonal antibodies involves pre-exposing, or priming, an animal
  • idiotype and also screening for immunoglobulin class (isotype), it is possible to select hybridoma clones that secrete the desired antibody.
  • transgenic animals harboring a functional heterologous immunoglobulin transgene are a method by which antibodies reactive with self antigens may be
  • the transgenic animal must produce transgenic B cells that are capable of maturing through the B lymphocyte development pathway. Such maturation requires the presence of surface IgM on the transgenic B cells, however isotypes other than IgM are desired for therapeutic uses.
  • transgenes and transgenic animals preferably include cis-acting sequences that
  • sequences for V(D)J joining are reportedly a highly conserved, near-palindromic heptamer and a less well conserved AT-rich nanomer separated by a spacer of either 12 or 23 bp (Tonegawa (1983), Nature, 302, 575-581; Hesse, et al. (1989), Genes in Dev. , 3, 1053-1061). Efficient recombination reportedly occurs only between sites containing recombination signal sequences with different length spacer regions.
  • mice [Buchini, et al. (1987), Nature. 326, 409-411 (unrearranged chicken ⁇ transgene); Goodhart, et al. (1987) , Proc. Natl. Acad. Sci. USA, 84, 4229-4233) (unrearranged rabbit k gene); and Bruggemann, et al. (1989), Proc. Natl. Acad. Sci. USA, 86, 6709-6713 (hybrid mouse-human heavy chain)].
  • the results of such experiments have been variable, in some cases, producing incomplete or minimal rearrangement of the
  • Fc portion of molecules such as the interaction with mast cells or basophils through Fee, and binding of complement by Fc ⁇ or Fc ⁇ , it further is desirable to generate a functional diversity of antibodies of a given specificity by variation of isotype.
  • transgenic animals have been generated that incorporate transgenes encoding one or more chains of a heterologous antibody, there have been no reports of hererologous transgenes that undergo successful isotype switching.
  • Transgenic animals that cannot switch isotypes are limited to producing h-iterologous antibodies of a single isotype, and more specifically are limited to producing an isotype that is essential for B cell maturation, such as IgM and possibly IgD, which may be of limited therapeutic utility.
  • IgM and possibly IgD an isotype that is essential for B cell maturation
  • transgenes and transgenic animals that are capable of
  • heterologous antibodies e.g. antibodies encoded by genetic sequences of a first species that are produced in a second species. More particularly, there is a need in the art for heterologous immunoglobulin transgenes and transgenic animals that are capable of undergoing functional V-D-J gene rearrangement that incorporates all or a portion of a D gene segment which contributes to recombinational diversity. Further, there is a need in the art for transgenes and transgenic animals that can support V-D-J recombination and isotype switching so that (1) functional B cell development may occur, and (2)
  • therapeutically useful heterologous antibodies may be any therapeutically useful heterologous antibodies.
  • transgenic nonhuman animals which are capable of producing a heterologous antibody, such as a human antibody.
  • heterologous antibodies wherein such B-cells are immortalized to provide a source of a monoclonal antibody specific for a particular antigen.
  • a further object of the invention is to provide methods to generate an immunoglobulin variable region gene segment repertoire that is used to construct one or more transgenes of the invention.
  • Transgenic nonhuman animals are provided which are capable of producing a heterologous antibody, such as a human antibody.
  • heterologous antibodies may be of various isotypes, including: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgA sec , IgD, of IgE.
  • the transgenic B cells and pre-B cells to produce surface-bound immunoglobulin, particularly of the IgM (or possibly IgD) isotype, in order to effectuate B cell development and
  • a cell of the B-cell lineage will produce only a single isotype at a time, although cis or trans
  • RNA splicing such as occurs naturally with the ⁇ s (secreted ⁇ ) and ⁇ M (membrane-bound ⁇ ) forms, and the ⁇ and ⁇ immunoglobulin chains, may lead to the contemporaneous
  • isotype switching may be classical class- switching or may result from one or more non-classical isotype switching mechanisms.
  • the invention provides heterologous immunoglobulin transgenes and transgenic nonhuman animals harboring such transgenes, wherein the transgenic animal is capable of producing heterologous antibodies of multiple isotypes by undergoing isotype switching.
  • Classical isotype switching occurs by recombination events which involve at least one switch sequence region in the transgene.
  • Non-classical isotype switching may occur by, for example, homologous recombination between human ⁇ and human ⁇ ⁇ sequences ( ⁇ - associated deletion).
  • Alternative non-classical switching mechanisms such as intertransgene and/or interchromosomal recombination, among others, may occur and effectuate isotype switching.
  • transgenic nonhuman animals produce a first immunoglobulin isotype that is necessary for antigen-stimulated B cell maturation and can switch to encode and produce one or more subsequent heterologous isotypes that have therapeutic and/or diagnostic utility.
  • nonhuman animals of the invention are thus able to produce, in one embodiment, IgG, IgA, and/or IgE antibodies that are encoded by human immunoglobulin genetic sequences and which also bind specific human antigens with high affinity.
  • the invention also encompasses B-cells from such transgenic animals that are capable of expressing heterologous antibodies of various isotypes, wherein such B-cells are immortalized to provide a source of a monoclonal antibody specific for a particular antigen.
  • Hybridoma cells that are derived from such B-cells can serve as one source of such heterologous monoclonal antibodies.
  • the invention provides heterologous unrearranged and rearranged immunoglobulin heavy and light chain transgenes capable of undergoing isotype switching in vivo in the
  • isotype switching may occur spontaneously or be induced by treatment of the transgenic animal or explanted B- lineage lymphocytes with agents that promote isotype
  • T-cell-derived lymphokines e.g., IL-4 and IFN ⁇
  • the invention includes methods to induce heterologous antibody production in the aforementioned transgenic non-human animal, wherein such antibodies may be of various isotypes.
  • These methods include producing an antigen- stimulated immune response in a transgenic nonhuman animal for the generation of heterologous antibodies, particularly heterologous antibodies of a switched isotype (i.e., IgG, IgA, and IgE).
  • heterologous immunoglobulins produced in the transgenic animal and monoclonal antibody clones derived from the B-cells of said animal may be of various isotypes.
  • This invention further provides methods that facilitate isotype switching of the transgene, so that
  • Switch regions may be grafted from various C H genes and ligated to other C H genes in a transgene construct; such grafted switch sequences will typically function independently of the
  • ⁇ -associated deletion sequences may be linked to various C H genes to effect non-classical switching by deletion of sequences between two ⁇ -associated deletion sequences.
  • a transgene may be constructed so that a particular C H gene is linked to a different switch sequence and thereby is switched to more frequently than occurs when the naturally associated switch region is used.
  • This invention also provides methods to determine whether isotype switching of transgene sequences has occurred in a transgenic animal containing an immunoglobulin transgene.
  • the invention provides immunoglobulin transgene constructs and methods for producing immunoglobulin transgene constructs, some of which contain a subset of germline
  • immunoglobulin loci sequences (which may include deletions).
  • the invention includes a specific method for facilitated cloning and construction of immunoglobulin transgenes,
  • restriction sites flanked by two unique NotI sites. This method exploits the complementary termini of Xhol and Sall restrictions sites and is useful for creating large constructs by ordered concatemerization of restriction fragments in a vector.
  • the transgenes of the invention include a heavy chain transgene comprising DNA encoding at least one variable gene segment, one diversity gene segment, one joining gene segment and one constant region gene segment.
  • immunoglobulin light chain transgene comprises DNA encoding at least one variable gene segment, one joining gene segment and one constant region gene segment.
  • the gene segments encoding the light and heavy chain gene segments are heterologous to the transgenic non-human animal in that they are derived from, or correspond to, DNA encoding immunoglobulin heavy and light chain gene segments from a species not consisting of the transgenic non-human animal.
  • the transgene is constructed such that the individual gene segments are unrearranged, i.e., not rearranged so as to encode a functional immunoglobulin light or heavy chain.
  • Such unrearranged transgenes permit recombination of the gene segments (functional rearrangement) and expression of the resultant rearranged immunoglobulin heavy and/or light chains within the transgenic non-human animal when said animal is exposed to antigen.
  • heterologous heavy and light immunoglobulin transgenes comprise relatively large fragments of unrearranged heterologous DNA. Such fragments typically comprise a substantial portion of the C, J (and in the case of heavy chain, D) segments from a heterologous immunoglobulin locus. In addition, such fragments also comprise a substantial portion of the variable gene segments.
  • regulatory sequences e.g. promoters, enhancers, class switch regions, recombination signals and the like, corresponding to sequences derived from the heterologous DNA.
  • regulatory sequences may be incorporated into the transgene from the same or a related species of the non-human animal used in the invention.
  • human immunoglobulin gene segments may be combined in a transgene with a rodent immunoglobulin enhancer sequence for use in a transgenic mouse.
  • a transgenic non-human animal containing germline unrearranged light and heavy immunoglobulin transgenes - that undergo VDJ joining during D-cell differentiation - is contacted with an antigen to induce production of a heterologous antibody in a secondary repertoire B-cell.
  • vectors and methods to disrupt the endogenous immunoglobulin loci in the non-human animal to be used in the invention utilize a transgene, preferably positive-negative selection vector, which is constructed such that it targets the functional disruption of a class of gene segments encoding a heavy and/or light immunoglobulin chain endogenous to the non-human animal used in the invention.
  • endogenous gene segments include diversity, joining and constant region gene segments.
  • the positive-negative selection vector is contacted, with at least one embryonic stem cell of a non-human animal after which cells are selected wherein the positive-negative selection vector has integrated into the genome of the non-human animal by way of homologous recombination.
  • the resultant transgenic non-human animal is substantially incapable of mounting an immunoglobulin-mediated immune response as a result of homologous integration of the vector into chromosomal DNA.
  • Such immune deficient non-human animals may thereafter be used for study of immune deficiencies or used as the recipient of heterologous immunoglobulin heavy and light chain transgenes.
  • the invention also provides vectors, methods, and compositions useful for suppressing the expression of one or more species of immunoglobulin chain(s), without disrupting an endogenous immunoglobulin locus. Such methods are useful for suppressing expression of one or more endogenous immunoglobulin chain(s), without disrupting an endogenous immunoglobulin locus. Such methods are useful for suppressing expression of one or more endogenous immunoglobulin chain(s), without disrupting an endogenous immunoglobulin locus. Such methods are useful for suppressing expression of one or more endogenous
  • immunoglobulin chains while permitting the expression of one or more transgene-encoded immunoglobulin chains.
  • suppression of immunoglobulin chain expression does not require the time-consuming breeding that is needed to
  • Ig chain suppression may be accomplished with: (1) transgenes encoding and expressing antisense RNA that specifically hybridizes to an endogenous Ig chain gene sequence, (2) antisense oligonucleotides that specifically hybridize to. an endogenous Ig chain gene
  • immunoglobulins that bind specifically to an endogenous Ig chain polypeptide.
  • Fig. 1 depicts the complementarity determining regions CDR1, CDR2 and CDR3 and framework regions FR1, FR2, FR3 and FR4 in unrearranged genomic DNA and mRNA expressed from a rearranged immunoglobulin heavy chain gene
  • Fig. 2 depicts the human ⁇ chain locus
  • Fig. 3 depicts. the human ⁇ chain locus
  • Fig. 4 depicts the human heavy chain locus
  • Fig. 5 depicts a transgene construct containing a rearranged IgM gene ligated to a 25 kb fragment that contains human ⁇ 3 and ⁇ 1 constant regions followed by a 700 bp fragment containing the rat chain 3' enhancer sequence.
  • Fig. 6 is a restriction map of the human ⁇ chain locus depicting the fragments to be used to form a light chain transgene by way of in vivo homologous recombination.
  • Fig. 7 depicts the construction of pGP1.
  • Fig. 8 depicts the construction of the polylinker contained in pGP1.
  • Fig. 9 depicts the fragments used to construct a human heavy chain transgene of the invention.
  • Fig. 10 depicts the construction of pHIG1 and pCON1.
  • Fig. 11 depicts the human C ⁇ l fragments which are inserted into pRE3 (rat enhancer 3') to form pREG2.
  • Fig. 12 depicts the construction of pHIG3' and PCON.
  • Fig. 13 depicts the fragment containing human D region segments used in construction of the transgenes of the invention.
  • Fig. 14 depicts the construction of pHIG2 (D segment. containing plasmid).
  • Fig. 15 depicts the fragments covering the human J ⁇ and human C ⁇ gene segments used in constructing a transgene of the invention.
  • Fig. 16 depicts the structure of pE ⁇ .
  • Fig. 17 depicts the construction of pKapH.
  • Figs. 18A through 18D depict the construction of a positive-negative selection vector for functionally disrupting the endogenous heavy chain immunoglobulin locus of mouse.
  • Figs. 19A through 19C depict the construction of a positive-negative selection vector for functionally disrupting the endogenous immunoglobulin light-chain loci in mouse.
  • Figs. 20 a through e depict the structure of a kappa light chain targeting vector.
  • Figs. 21 a through f depict the structure of a mouse heavy chain targeting vector.
  • Fig. 22 depicts the map of vector pGPe.
  • Fig. 23 depicts the structure of vector pJM2.
  • Fig. 24 depicts the structure of vector pCOR1.
  • Fig. 25 depicts the transgene constructs for pIGM1, pHC1 and pHC2.
  • Fig. 26 depicts the structure of p ⁇ e2.
  • Fig. 27 depicts the structure of pVGE1.
  • Fig. 28 depicts the assay results of human Ig expression in a pHC1 transgenic mouse.
  • Fig,. 29 depicts the structure of pJCK1.
  • Fig. 30 depicts the construction of a synthetic heavy chain variable region.
  • Fig. 31 is a schematic representation of the ' heavy chain minilocus constructs pIGM 1 , pHC1, and pHC2.
  • Fig. 32 is a schematic representation of the heavy chain minilocus construct pIGG1 and the ⁇ light chain
  • Fig. 33 depicts a scheme to reconstruct functionally rearranged light chain genes.
  • Fig. 34 depicts serum ELISA results
  • Fig. 35 depicts the results of an ELISA assay of serum from 8 transgenic mice.
  • Fig. 36 is a schematic representation of plasmid pBCE1.
  • Fig. 37 depicts the immune response of transgenic mice of the present invention against KLH-DNP, by measuring IgG and IgM levels specific for KLH-DNP (37A), KLH (37B) and BSA-DNP (37C).
  • Fig. 38 shows ELISA data demonstrating the presence of antibodies that bind human carcinoembryonic antigen (CEA) and comprise human ⁇ chains; each panel shows reciprocal serial dilutions from pooled serum samples obtained from mice on the indicated day following immunization.
  • CEA carcinoembryonic antigen
  • Fig. 39 shows ELISA data demonstrating the presence of antibodies that bind human carcinoembryonic antigen (CEA) and comprise human ⁇ chains; each panel shows reciprocal serial dilutions from pooled serum samples obtained from mice on the indicated day following immunization.
  • CEA carcinoembryonic antigen
  • Fig. 40 shows aligned variable region sequences of 23 randomly-chosen cDNAs generated from mRNA obtained from lymphoid tissue of HCI transgenic mice immunized, with human carcinoembryonic antigen (CEA) as compared to the germline transgene sequence (top line); on each line nucleotide changes relative to germline sequence are shown above the alteration in deduced amino acid sequence (if any); the regions
  • Non-germline encoded nucleotides are shown in capital letters.
  • Germline V H 251 and J H are shown in lower case letters.
  • Deduced amino acid changes are given beneath
  • Fig. 41 shows the data from Fig. 40 in histogram format; deduced amino acid residue position is shown as the ordinate (left is the amino-terminal direction, right is in the direction towards the carboxy-terminus) and frequency of sequence variation is shown as the abscissa.
  • Fig. . 42 show the nucleotide sequence of a human DNA fragment, designated vk65.3, containing a V ⁇ gene segment; the deduced amino acid sequences of the V ⁇ coding regions are also shown; splicing and recombination signal sequences
  • Fig. 43 show the nucleotide sequence of a human DNA fragment, designated vk65.5, containing a V ⁇ gene segment; the deduced amino acid sequences of the V ⁇ coding regions are also shown; splicing and recombination signal sequences
  • Fig. 44 show the nucleotide sequence of a human DNA fragment, designated vk65.8, containing a V ⁇ gene segment; the deduced amino acid sequences of the V ⁇ coding regions are also shown; splicing and recombination signal sequences
  • Fig. 45 show the nucleotide sequence of a human DNA fragment, designated vk65.15, containing a V ⁇ gene segment; the deduced amino acid sequences of the V ⁇ coding regions are also shown; splicing and recombination signal sequences
  • Fig. 46 shows formation of a light chain minilocus by homologous recombination between two overlapping fragments which were co-injected.
  • Table 1 depicts the sequence of vector pGPe.
  • Table 2 depicts the sequence of gene V H 4 .8.
  • Table 3 depicts the detection of human IgM and IgG in the serum of transgenic mice of this invention.
  • Table 4 depicts sequences of VDJ joints.
  • Table 5 depicts the distribution of J segments incorporated into pHC1 transgene encoded transcripts to J segments found in adult human peripheral blood lymphocytes (PBL).
  • Table 6 depicts the distribution of D segments incorporated into pHC1 transgene encoded transcripts to D segments found in adult human peripheral blood lymphocytes (PBL).
  • Table 7 depicts the length of the CDR3 peptides from transcripts with in-frame VDJ joints in the pHC1 transgenic mouse and in human PBL.
  • Table 8 depicts the predicted amino acid sequences of the VDJ regions from 30 clones analyzed from a pHC1
  • Table 9 shows transgenic mice of line 112 that were used in the indicated experiments; (+) indicates the presence of the respective transgene, (++) indicates that the animal is homozygous for the J H D knockout transgene.
  • human immunoglobulins that are reactive with specific human antigens that are promising therapeutic and/or diagnostic targets.
  • producing human immunoglobulins that bind specifically with human antigens is problematic.
  • the immunized animal that serves as the source of B cells must make an immune response against the presented antigen.
  • the antigen presented In order for an animal to make an immune response, the antigen presented must be foreign and the animal must not be tolerant to the antigen.
  • self-tolerance will prevent an immunized human from making a substantial immune response to the human protein, since the only epitopes of the antigen that may be immunogenic will be those that result from polymorphism of the protein within the human population
  • B-cells for forming a hybridoma (a human in the illustrative given example) does make an immune response against an
  • One methodology that can be used to obtain human antibodies that are specifically reactive with human antigens is the production of a transgenic mouse harboring the human immunoglobulin transgene constructs of this invention.
  • transgenes containing all or portions of the human immunoglobulin heavy and light chain loci or transgenes containing synthetic "miniloci" (described infra, and in
  • transgenic nonhuman animal which comprise essential functional elements of the human heavy and light chain loci, are employed to produce a transgenic nonhuman animal.
  • a transgenic nonhuman animal will have the capacity to produce immunoglobulin chains that are encoded by human immunoglobulin genes, and additionally will be capable of making an immune response against human antigens.
  • transgenic animals can serve as a source of immune sera reactive with specified human antigens, and B-cells from such transgenic animals can be fused with myeloma cells to produce hybridomas that secrete monoclonal antibodies that are encoded by human, immunoglobulin genes and which are specifically reactive with human antigens.
  • transgenic mice containing various forms of immunoglobulin genes has been reported previously.
  • Rearranged mouse immunoglobulin heavy or light chain genes have been used to produce transgenic mice.
  • functionally rearranged human Ig genes including the ⁇ or ⁇ 1 constant region have been expressed in transgenic mice.
  • V-D-J or V-J not rearranged immunoglobulin genes have been variable, in some cases, producing incomplete or minimal rearrangement of the transgene.
  • immunoglobulin transgenes which undergo successful isotype switching between C H genes within a transgene.
  • antibody refers to a glycoprotein comprising at least two light polypeptide chains and two heavy polypeptide chains. Each of the heavy and light polypeptide chains contains a variable region (generally the amino terminal portion of the polypeptide chain) which
  • Each of the heavy and light polypeptide chains also comprises a constant region of the polypeptide chains (generally the carboxyl terminal portion) which may mediate the binding of the immunoglobulin to host tissues or factors including
  • a heterologous antibody is defined in relation to the transgenic non-human organism producing such an antibody. It is defined as an antibody having an amino acid sequence or an encoding DNA sequence corresponding to that found in an organism not consisting of the transgenic non-human animal.
  • hybrid antibody refers to an antibody having a light and heavy chains of different organismal origins.
  • an antibody having a human heavy chain associated with a murine light chain is a
  • isotype refers to the antibody class (e.g., IgM or IgG 1 ) that is encoded by heavy chain constant region genes.
  • isotype switching refers to the phenomenon by which the class, or isotype, of an antibody changes from one Ig class to one of the other Ig classes.
  • nonswitched isotype refers to the isotypic class of heavy chain that is produced when no isotype switching has taken place; the C H gene encoding the
  • nonswitched isotype is typically the first C H gene immediately downstream from the functionally rearranged VDJ gene.
  • switch sequence refers to those DNA sequences responsible for switch recombination.
  • a "switch donor” sequence typically a ⁇ switch region, will be 5' (i.e., upstream) of the construct region to be deleted during the switch recombination.
  • the "switch acceptor” region will be between the construct region to be deleted and the replacement constant region (e.g., ⁇ , ⁇ , etc.). As there is no specific site where recombination always occurs, the final gene sequence will typically not be predictable from the construct.
  • glycosylation pattern is defined as the pattern of carbohydrate units that are covalently attached to a protein, more specifically to an immunoglobulin protein.
  • a glycosylation pattern of a heterologous antibody can be characterized as being substantially similar to
  • glycosylation patterns which occur naturally on antibodies produced by the species of the nonhuman transgenic animal, when one of ordinary skill in the art- would recognize the glycosylation pattern of the heterologous antibody as being more similar to said pattern of glycosylation in the species of the nonhuman transgenic animal than to the species from which the C H genes of the transgene were derived.
  • telomere binding refers to the property of the antibody: (1) to bind to a predetermined antigen with an affinity of at least 1 x 10 7 M -1 , and (2) to preferentially bind to the predetermined antigen with an affinity that is at least twc-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen.
  • a non-specific antigen e.g., BSA, casein
  • naturally-occurring refers to the fact that an object can be found in nature.
  • a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally-occurring.
  • rearranged refers to a configuration of a heavy chain or light chain immunoglobulin locus wherein a V segment is positioned immediately adjacent to a D-J or J segment in a conformation encoding essentially a complete V H or V L domain, respectively.
  • immunoglobulin gene locus can be identified by comparison to germline DNA; a rearranged locus will have at least one recombined heptamer/nonamer homology element.
  • V segment configuration refers to the configuration wherein the V segment is not recombined so as to be immediately adjacent to a D or J segment.
  • the transgenes of the invention are constructed so as to produce isotype switching and one or more of the following: (1) high level and cell-type specific expression, (2) functional gene rearrangement, (3) activation of and response to allelic exclusion, (4) expression of a sufficient primary repertoire, (5) signal transduction, (6) somatic hypermutation, and (7) domination of the transgene antibody locus during the immune response.
  • the transgene need not activate allelic exclusion.
  • the transgene comprises a
  • transgenic non-human animals contain rearranged, unrearranged or a combination of rearranged and unrearranged heterologous immunoglobulin heavy and light chain transgenes in the
  • Each of the heavy chain transgenes comprises at least one C H gene.
  • the heavy chain transgene may contain functional isotype switch sequences, which are capable of supporting isotype switching of a heterologous transgene encoding multiple C H genes in B- cells of the transgenic animal.
  • Such switch sequences may be those which occur naturally in the germline immunoglobulin locus from the species that serves as the source of the transgene C H genes, or such switch sequences may be derived from those which occur in the species that is to receive the transgene construct (the transgeneic animal).
  • a human transgene construct that is used to produce a transgenic mouse may produce a higher frequency of isotype switching events if it incorporates switch sequences similar to those that occur naturally in the mouse heavy chain locus, as presumably the mouse switch sequences are optimized to
  • Switch sequences made be isolated and cloned by conventional cloning methods, or may be synthesized de novo from overlapping synthetic oligonucleotides designed on the basis of published sequence information relating to immunoglobulin switch region sequences (Mills et al., Nucl. Acids Res. 18:7305-7316 (1991);
  • heterologous heavy and light chain immunoglobulin transgenes are found in a significant fraction of the B-cells of the transgenic animal (at least 10 percent).
  • the transgenes of the invention include a heavy chain transgene comprising DNA encoding at least one variable gene segment, one diversity gene segment, one joining gene segment and at least one constant region gene segment.
  • the immunoglobulin light chain transgene comprises DNA encoding at least one variable gene segment, one joining gene segment and at least one constant region gene segment.
  • the gene segments encoding the light and heavy chain gene segments are
  • the transgene is constructed such that the individual gene segments are unrearranged, i.e., not rearranged so as to encode a functional immunoglobulin light or heavy chain.
  • unrearranged transgenes support
  • V, D, and J gene segments preferably support incorporation of all ora portion of a D region gene segment in the resultant
  • the transgenes comprise an unrearranged "mini-locus". Such transgenes typically comprise an unrearranged "mini-locus". Such transgenes typically comprise an unrearranged "mini-locus". Such transgenes typically comprise an unrearranged "mini-locus". Such transgenes typically comprise an unrearranged "mini-locus". Such transgenes typically comprise an unrearranged "mini-locus". Such transgenes typically comprise
  • the various regulatory sequences e.g. promoters, enhancers, class switch regions, splice-donor and splice- acceptor sequences for RNA processing, recombination signals and the like, comprise corresponding sequences derived from the heterologous DNA.
  • Such regulatory sequences may be incorporated into the transgene from the same or a related species of the non-human animal used in the invention.
  • human immunoglobulin gene segments may be combined in a transgene with a rodent immunoglobulin enhancer sequence for use in a transgenic mouse.
  • synthetic regulatory sequences may be incorporated into the transgene, wherein such synthetic regulatory sequences are not homologous to a
  • Synthetic regulatory sequences are designed according to consensus rules, such as, for example, those specifying the permissible sequences of a splice- acceptor site or a promoter/enhancer motif.
  • the invention also includes transgenic animals containing germ line cells having a heavy and light transgene wherein one of the said transgenes contains rearranged gene segments with the other containing unrearranged gene segments.
  • the rearranged transgene is a light chain immunoglobulin transgene and the unrearranged transgene is a heavy chain immunoglobulin transgene.
  • the basic structure of all immunoglobulins is based upon a unit consisting of two light polypeptide chains and two heavy polypeptide chains. Each light chain comprises two regions known as the variable light chain region and the constant light chain region. Similarly, the immunoglobulin heavy chain comprises two regions designated the variable heavy chain region and the constant heavy chain region.
  • the constant region for the heavy or light chain is encoded by genomic sequences referred to as heavy or light constant region gerie (C H ) segments.
  • C H heavy or light constant region gerie
  • the use of a particular heavy chain gene segment defines the class of immunoglobulin.
  • the ⁇ constant region gene segments define the IgM class of antibody whereas the use of a ⁇ , ⁇ 2, ⁇ 3 or ⁇ 4 constant region gene segment defines the IgG class of antibodies as well as the IgG subclasses IgG1 through IgG4.
  • the use of a ⁇ 1 or ⁇ 2 constant region gene segment defines the IgA class of antibodies as well as the subclasses IgA1 and IgA2.
  • the ⁇ and e constant region gene segments define the IgD and IgE antibodv classes, respectively.
  • immunoglobulin chains together contain the antigen binding domain of the antibody. Because of the need for diversity in this region of the antibody to permit binding to a wide range of antigens, the DNA encoding the initial or primary
  • repertoire variable region comprises a number of different DNA segments derived from families of specific variable region gene segments.
  • families comprise variable (V) gene segments and joining (J) gene segments.
  • V variable
  • J joining
  • the initial variable region of the light chain is encoded by one V gene segment and one J gene segment each selected from the family of V and J gene segments contained in the genomic DNA of the organism.
  • the DNA encoding the initial or primary repertoire variable region of the heavy chain comprises one heavy chain V gene segment, one heavy chain diversity (D) gene segment and one J gene segment, each selected from the appropriate V, D and J families of
  • a heavy chain transgene include cis-acting sequences that support functional V-D-J rearrangement that can incorporate all or part of a D region gene sequence in a rearranged V-D-J gene sequence. Typically, at least about 1 percent of
  • transgene-encoded heavy chains include recognizable D region sequences in the V region.
  • at least about 10 percent of transgene-encoded V regions include recognizable D region sequences, more preferably at least about 30 percent, and most preferably more than 50 percent include recognizable D region sequences.
  • a recognizable D region sequence is generally at least about eight consecutive nucleotides corresponding to a sequence present in a D region gene segment of a heavy chain transgene and/or the amino acid sequence encoded by such D region nucleotide sequence. For example, if a transgene includes the D region gene DHQ52, a transgene-encoded mRNA containing the sequence 5'-TAACTGGG-3' located in the V region between a V gene segment sequence and a J gene segment
  • a transgene includes the D region gene DHQ52
  • a transgeneencoded heavy chain polypeptide containing the amino acid sequence -DAF- located in the V region between a V gene segment amino acid sequence and a J gene segment amino acid sequence is recognizable as containing a D region sequence, specifically a DHQ52 sequence.
  • D region sequences may be recognizable but may not correspond identically to a consecutive D region sequence in the transgene.
  • CTAAXTGGGG-3' where X is A, T, or G, and which is located in a heavy chain V region and flanked by a V region gene sequence and a J region gene sequence, can be recognized as
  • polypeptide sequences -DAFDI-, -DYFDY-, or -GAFDI- located in a V region and flanked on the amino-terminal side by an amino acid sequence encoded by a transgene V gene sequence and flanked on the carboxyterminal side by an amino acid sequence encoded by a transgene J gene sequence is recognizable as a D region sequence.
  • an amino acid sequence or nucleotide sequence is recognizable as a D region sequence if: (1) the sequence is located in a V region and is flanked on one side by a V gene sequence (nucleotide sequence or deduced amino acid sequence) and on the other side by a J gene sequence (nucleotide sequence or deduced amino acid sequence) and (2) the sequence is substantially identical or substantially similar to a known D gene sequence (nucleotide sequence or encoded amino acid sequence).
  • substantially identical denotes a characteristic of a polypeptide sequence or nucleic acid sequence, wherein the polypeptide sequence has at least 50 percent sequence identity compared to a reference sequence, and the nucleic acid sequence has at least 70 percent sequence identity compared to a reference sequence.
  • the percentage of sequence identity is calculated excluding small deletions or additions which total less than 35 percent of the reference sequence.
  • the reference sequence may be a subset of a larger sequence, such as an entire D gene; however, the reference sequence is at least 8 nucleotides long in the case of
  • the reference sequence is at least 8 to 12 nucleotides or at least 3 to 4 amino acids, and preferably the reference sequence is 12 to 15 nucleotides or more, or at least 5 amino acids.
  • substantially similarity denotes a characteristic of an polypeptide sequence, wherein the
  • polypeptide sequence has at least 80 percent similarity to a reference sequence.
  • the percentage of sequence similarity is calculated by scoring identical amino acids or positional conservative amino acid substitutions as similar.
  • positional conservative amino acid substitution is one that can result from a single nucleotide substitution; a first amino acid is replaced by a second amino acid where a codon for the first amino acid and a codon for the second amino acid can differ by a single nucleotide substitution.
  • sequence -Lys-Glu-Arg-Val- is substantially similar to the sequence -Asn-Asp-Ser-Val-, since the codon sequence -AAA-GAA-AGA-GUU- can be mutated to -AAC-GAC-AGC-GUU- by introducing only 3 substitution mutations, single
  • the reference sequence may be a subset of a larger sequence. such as an entire D gene; however, the reference sequence is at least 4 amino residues long. Typically, the reference sequence is at least 5 amino acids, and preferably the
  • reference sequence is 6 amino acids or more.
  • immunoglobulin gene segments the V, D, J and constant (C) gene segments are found, for the most part, in clusters of V, D, J and C gene segments in the precursors of primary
  • RSS's recombination signal sequences
  • V, D and J segments flank recombinationally competent V, D and J segments.
  • RSS's necessary and sufficient to direct recombination comprise a dyad-symmetric heptamer, an AT-rich nonamer and an intervening spacer region of either 12 or 23 base pairs.
  • each V and D gene segment comprises the sequence CACAGTG or its analogue followed by a spacer of unconserved sequence and then a nonamer having the sequence ACAAAAACC or its analogue. These sequences are found on the J, or downstream side, of each V and D gene segment. Immediately preceding the germline D and J segments are again two recombination signal sequences, first the nonamer and then the heptamer again separated by an unconserved sequence. The heptameric and nonameric sequences following a V L , V H or D segment are complementary to those preceding the J L , D or J H segments with which they recombine. The spacers between the heptameric and nonameric sequences are either 12 base pairs long or between 22 and 24 base pairs long.
  • variable recombination between the V and J segments in the light chain and between the D and J segments of the heavy chain.
  • Such variable recombination is generated by variation in the exact place at which such segments are joined.
  • variation in the light chain typically occurs within the last codon of the V gene segment and the first codon of the J segment.
  • Similar imprecision in joining occurs on the heavy chain chromosome between the D and J H segments and may extend over as many as 10 nucleotides.
  • nucleotides may be inserted between the D and J H and between the V H and D gene segments which are not encoded by genomic DNA.
  • the addition of these nucleotides is known as N-region diversity.
  • RNA transcript After VJ and/or VDJ rearrangement, transcription of the rearranged variable region and one or more constant region gene segments located downstream from the rearranged variable region produces a primary RNA transcript which upon
  • RNA splicing results in an mRNA which encodes a full length heavy or light immunoglobulin chain.
  • heavy and light chains include a leader signal sequence to effect secretion through and/or insertion of the immunoglobulin into the transmembrane region of the B-cell.
  • the DNA encoding this signal sequence is contained within the first exon of the V segment used to form the variable region of the heavy or light immunoglobulin chain.
  • Appropriate regulatory sequences are also present in the mRNA to control translation of the mRNA to produce the encoded heavy and light immunoglobulin
  • polypeptides which upon proper association with each other form an antibody molecule.
  • variable region gene segments and the variable recombination which may occur during such joining is the production of a primary antibody repertoire.
  • each B-cell which has differentiated to this stage produces a single primary repertoire antibody.
  • cellular events occur which suppress the functional
  • allelic exclusion The process by which diploid B-cells maintain such mono-specificity is termed allelic exclusion.
  • B-cell clones expressing immunoglobulins from within the set of sequences comprising the primary repertoire are immediately available to respond to foreign antigens. Because of the limited diversity generated by simple VJ and VDJ joining, the antibodies produced by the so-called primary response are of relatively low affinity.
  • Two different types of B-cells make up this initial response: precursors of primary antibody-forming cells and precursors of secondary repertoire B-cells (Linton et al., Cell 59:1049-1059 (1989)).
  • the first type of B-cell matures into IgM-secreting plasma cells in response to certain antigens.
  • the other B-cells respond to initial exposure to antigen by entering a T-cell dependent maturation pathway.
  • the structure of the antibody molecule on the cell surface changes in two ways: the constant region switches to a non-IgM subtype and the sequence of the variable region can be modified by multiple single amino acid substitutions to produce a higher affinity antibody molecule.
  • variable region of a heavy or light Ig chain contains an antigen binding domain. It has been determined by amino acid and nucleic acid
  • CDRl, CDR2 and CDR3 also referred to as hypervariable regions 1, 2 and 3
  • the CDR1 and CDR2 are located within the variable gene segment whereas the CDR3 is largely the result of recombination between V and J gene segments or V, D and J gene segments.
  • Those portions of the variable region which do not consist of CDR1, 2 or 3 are commonly referred to as framework regions designated FR1, FR2, FR3 and FR4. See Fig. 1.
  • framework regions designated FR1, FR2, FR3 and FR4
  • rearranged DNA is mutated to give rise to new clones with altered Ig molecules.
  • Those clones with higher affinities for the foreign antigen are selectively expanded by helper
  • Transgenic non-human animals in one aspect of the invention are produced by introducing at least one of the immunoglobulin transgenes of the invention (discussed
  • non-human animals which are used in the invention generally comprise any mammal which is capable of rearranging immunoglobulin gene segments to produce a primary antibody response.
  • nonhuman transgenic animals may include, for example, transgenic pigs, transgenic rats, transgenic rabbits, transgenic cattle, and other transgenic animal species, particularly mammalian species, known in the art.
  • particularly preferred non-human animal is the mouse or other members of the rodent family.
  • mice any non-human mammal which is capable of mounting a primary and secondary antibody response may be used.
  • Such animals include non-human primates, such as chimpanzee, bovine, ovine, and porcine species, other members of the rodent family, e.g. rat, as well as rabbit and guinea pig.
  • Particular preferred animals are mouse, rat, rabbit and guinea pig, most preferably mouse.
  • various gene segments from the human genome are used in heavy and light chain transgenes in an unrearranged form.
  • such transgenes are introduced into mice.
  • the unrearranged gene segments of the light and/or heavy chain transgene have DNA sequences unique to the human species which are
  • the transgenes comprise rearranged heavy and/or light
  • transgenes corresponding to functionally rearranged VDJ or VJ segments contain immunoglobulin DNA sequences which are also clearly distinguishable from the endogenous immunoglobulin gene segments in the mouse.
  • sequences may be detected in the transgenic non-human animals of the invention with antibodies specific for immunoglobulin epitopes encoded by human immunoglobulin gene segments.
  • Transgenic B-cells containing unrearranged transgenes from human or other species functionally recombine the appropriate gene segments to form functionally rearranged light and heavy chain variable regions. It will be readily apparent that the antibody encoded by such rearranged
  • transgenes has a DNA and/or amino acid sequence which i ⁇ heterologous to that normally encountered in the nonhuman animal used to practice the indention.
  • an "unrearranged immunoglobulin heavy chain transgene” comprises DNA encoding at least one variable gene segment, one diversity gene segment, one joining gene segment and one constant region gene segment.
  • Each of the gene segments of said heavy chain transgene are derived from, or has a sequence corresponding to, DNA encoding
  • an "unrearranged immunoglobulin light chain transgene” comprises DNA encoding at least one variable gene segment, one joining gene segment and at least one constant region gene segment wherein each gene segment of said light chain tr; nsgene is derived from, or has a sequence corresponding to, DNA encoding immunoglobulin light chain gene segments from a species not consisting of the non-human animal into which said light chain transgene is introduced.
  • Such heavy and light chain transgenes in this aspect of the invention contain the above-identified gene segments in an unrearranged form.
  • interposed between the V, D and J segments in the heavy chain transgene and between the V and J segments on the light chain transgene are appropriate.
  • transgenes also include appropriate RNA splicing signals to join a constant region gene segment with the VJ or VDJ
  • switch regions are incorporated upstream from each of the constant region gene segments and downstream from the variable region gene segments to permit recombination between such constant regions to allow for immunoglobulin class switching, e.g. from IgM to IgG.
  • switch regions are incorporated upstream from each of the constant region gene segments and downstream from the variable region gene segments to permit recombination between such constant regions to allow for immunoglobulin class switching, e.g. from IgM to IgG.
  • immunoglobulin transgenes also contain transcription control sequences including promoter regions situated upstream from the variable region gene segments which typically contain TATA motifs.
  • a promoter region can be defined approximately as a DNA sequence that, when operably linked to a downstream sequence, can produce transcription of the downstream
  • Promoters may require the presence of additional linked cis-acting sequences in order to produce efficient transcription.
  • other sequences that participate in the transcription of sterile transcripts are preferably included. Examples of sequences that participate in
  • sequences typically include about at least 50 bp immediately upstream of a switch region, preferably about at least 200 bp upstream of a switch region; and more preferably about at least 200-1000 bp or more upstream of a switch region.
  • Suitable sequences occur immediately upstream of the human S ⁇ 1 , S ⁇ 2 , S ⁇ 3 , S ⁇ 4 , S ⁇ 1 , S ⁇ 2 , and S ⁇ switch regions, although the sequences immediately upstream of the human S ⁇ 1 , and S ⁇ 3 switch regions are preferable.
  • interferon (IFN) inducible transcriptional regulatory elements such as IFN-inducible enhancers, are preferably included immediately upstream of transgene switch sequences.
  • promoters In addition to promoters, other regulatory sequences which function primarily in B-lineage cells are used. Thus, for example, a light chain enhancer sequence situated
  • regulatory enhancers are used to maximize the transcription and translation of the transgene so as to induce allelic exclusion and to provide relatively high levels of transgene expression.
  • regulatory control sequences have been generically described, such regulatory sequences may be heterologous to the nonhuman animal being derived from the genomic DNA from which the heterologous transgene immunoglobulin gene segments are obtained. Alternately, such regulatory gene segments are derived from the corresponding regulatory sequences in the genome of the non-human animal, or closely related species, which contains the heavy and light transgene.
  • gene segments are derived from human beings.
  • the transgenic non-human animals harboring such heavy and light transgenes are capable of mounting an Ig-mediated immune response to a specific antigen administered to such an animal.
  • B-cells are produced within such an animal which are capable of producing heterologous human antibody.
  • an appropriate monoclonal antibody e.g. a hybridoma
  • a source of therapeutic human monoclonal antibody is provided.
  • Such human Mabs have significantly reduced immunogenicity when therapeutically administered to humans.
  • transgenic nonhuman animals contain functionally at least one rearranged
  • heterologous heavy chain immunoglobulin transgene in the germline of the transgenic animal.
  • Such animals contain primary repertoire B-cells that express such rearranged heavy transgenes.
  • B-cells preferably are capable of undergoing somatic mutation when contacted with an antigen to form a heterologous antibody having high affinity and specificity for the antigen.
  • Said rearranged transgenes will contain at least two C H genes and the associated sequences required for isotype switching.
  • the invention also includes transgenic animals containing germ line cells having heavy and light transgenes wherein one of the said transgenes contains rearranged gene segments with the other containing unrearranged gene segments.
  • the heavy chain transgenes shall have at least two C H genes and the associated sequences required for isotype switching.
  • the invention further includes methods for generating a synthetic variable region gene segment repertoire to be used in the transgenes of the invention.
  • the method comprises generating a population of immunoglobulin V segment DNAs wherein each of the V segment DNAs encodes an
  • immunoglobulin V segment contains at each end a cleavage recognition site of a restriction endonuclease.
  • Such synthetic variable region heavy chain transgenes shall have at least two C H genes and the associated sequences required for isotype switching.
  • the cell In the development of a B lymphocyte, the cell initially produces IgM with a binding specificity determined by the productively rearranged V H and V L regions.
  • each B cell and its progeny cells synthesize antibodies with the same L and H chain V regions, but they may switch the isotype of the H chain.
  • This gene rearrangement process typically occurs by recombination between so called switch segments located immediately upstream of each heavy chain gene (except S) .
  • the individual switch segments are between 2 and 10 kb in length, and consist primarily of short repeated sequences.
  • the switch (S) region of the ⁇ gene, S ⁇ is located about 1 to 2 kb 5' to the coding sequence and is composed of numerous tandem repeats of sequences of the form
  • All the sequenced S regions include numerous occurrences of the pentamers GAGCT and GGGGT that are the basic repeated elements of the S gene (T. Nikaido et al., J. Biol. Chem. 257:7322- 7329 (1982) which is incorporated herein by reference); in the other S regions these pentamers are not precisely tandemly repeated as in S ⁇ , but instead are embedded in larger repeat units.
  • the S ⁇ 1 region has an additional higher-order
  • Switch regions of human H chain genes have been found to be very similar to their mouse homologs. Indeed, similarity between pairs of human and mouse clones 5' to the C H genes has been found to be confined to the S regions, a fact that confirms the biological significance of these regions.
  • a switch recombination between ⁇ and a genes produces a composite S ⁇ -S ⁇ sequence.
  • the switch machinery can apparently accommodate different alignments of the repeated homologous regions of germline S precursors and then join the sequences at different positions within the alignment.
  • the switch machinery can apparently accommodate different alignments of the repeated homologous regions of germline S precursors and then join the sequences at different positions within the alignment.
  • cytokines might upregulate isotype-specific recombinases, it is also possible that the same enzymatic machinery catalyzes switches to all isotypes and that specificity lies in
  • T-cell-derived lymphokines IL-4 and IFN ⁇ have been shown to specifically promote the expression of certain isotypes: IL-4 decreases IgM, IgG2a, IgG2b, and IgG3
  • IgE and IgG1 expression increases IgE and IgG1 expression; while IFN ⁇ selectively stimulates IgG2a expression and antagonizes the IL-4-induced increase in IgE and IgG1 expression (Coffman et al., J. Immunol. 136:949-954 (1986) and Snapper et al.,
  • lymphokines actually promote switch recombination.
  • the observed induction of the ⁇ I sterile transcript by IL-4 and inhibition by IFN- ⁇ correlates with the observation that IL-4 promotes class switching to ⁇ 1 in B-cells in culture, while IFN- ⁇ inhibits ⁇ 1 expression. Therefore, the inclusion of regulatory sequences that affect the transcription of sterile transcripts may also affect the rate of isotype switching. For example, increasing the transcription of a particular sterile transcript typically can be expected to enhance the frequency of isotype switch
  • transgenes incorporate transcriptional regulatory sequences within about 1-2 kb upstream of each switch region that is to be utilized for isotype switching.
  • These transcriptional regulatory sequences preferably include a promoter and an enhancer element, and more preferably include the 5' flanking (i.e., upstream) region that is naturally associated (i.e., occurs in germline configuration) with a switch region. This 5' flanking (i.e., upstream) region that is naturally associated (i.e., occurs in germline configuration) with a switch region. This 5'
  • flanking region is typically about at least 50 nucleotides in length, preferably about at least 200 nucleotides in length, and more preferably at least 500-1000 nucleotides.
  • each switch region incorporated in the transgene construct have the 5' flanking region that occurs immediately upstream in the naturally occurring germline configuration.
  • transgene function An important requirement for transgene function is the generation of a primary antibody repertoire that is diverse enough to trigger a secondary immune response for a wide range of antigens.
  • V region proximal constant regions are deleted leading to the
  • RNA splicing For each heavy chain . class, alternative patterns of RNA splicing give rise to both transmembrane and secreted immunoglobulins.
  • the human heavy chain locus consists of
  • immunoglobulin heavy and light chain transgenes comprise unrearranged genomic DNA from humans.
  • a preferred transgene comprises a NotI fragment having a length between 670 to 830 kb. The length of this fragment is ambiguous because the 3' restriction site has not been accurately mapped. It is known, however, to reside between the ⁇ l and gene segments. This fragment contains members of all six of the known V H families, the D and J gene segments, as well as the ⁇ , ⁇ , ⁇ 3 , ⁇ 1 and ⁇ 1 constant regions (Berman et al., EMBO J. 7:727-738 (1988), which is incorporated herein by reference).
  • IgM B-cell development
  • IgG 1 switched heavy chain class
  • a genomic fragment containing all of the necessary gene segments and regulatory sequences from a human light chain locus may be similarly constructed. Such transgenes are constructed as described in the Examples.
  • immunoglobulin heavy chain locus may be formed in vivo in the non-human animal during transgenesis.
  • Such in vivo transgene construction is produced by introducing two or more
  • fragments have DNA sequences which are substantially identical
  • In vivo transgene construction can be used to form any number of immunoglobulin transgenes which because of their size are otherwise difficult, or impossible, to make or manipulate by present technology.
  • in vivo transgene construction is useful to generate immunoglobulin transgenes which are larger than DNA fragments which may be manipulated by YAC vectors (Murray and Szostak, Nature 305: 189-193
  • Such in vivo transgene construction may be used to introduce into a non-human animal substantially the entire immunoglobulin loci from a species not consisting of the transgenic non-human animal.
  • in vivo homologous recombination may also be utilized to form "mini-locus" transgenes as described in the Examples.
  • portions of the DNA fragments preferably comprise about 500 bp to about 2000 bp, most preferably 1.0 kb to 2.0 kb.
  • immunoglobulin minilocus refers to a DNA sequence (which may be within a longer
  • DNA sequence usually of less than about 150 kb, typically between about 25 and 100 kb, containing at least one each of the following: a functional variable (V) gene segment, a functional joining (J) region segment, at least one functional constant (C) region gene segment, and--if it is a heavy chain minilocus--a functional diversity (D) region segment, such that said DNA sequence contains at least one substantial discontinuity (e.g., a deletion, usually of at least about 2 to 5 kb, preferably 10-25 kb or more, relative to the
  • a light chain minilocus transgene will be at least 25 kb in length, typically 50 to 60 kb.
  • a heavy chain transgene will typically be about 70 to 80 kb in length, preferably at least about 60 kb with two
  • the individual elements of the minilocus are preferably in the germline configuration and capable of undergoing gene rearrangement in the pre-B cell of a
  • transgenic animal so as to express functional antibody
  • a heavy chain minilocus comprising at least two C H genes and the requisite switching sequences is typ.cally c pable of undergoing isotype switching, so that functional antibody molecules of different immunoglobulin classes will be generated.
  • switching may occur in vivo in B-cells residing within the transgenic nonhuman animal, or may occur in cultured cells of the B-cell lineage which have been explanted from the
  • immunoglobulin heavy chain transgenes comprise one or more of each of the V H , D, and J H gene segments and two or more of the C H genes. At least one of each appropriate type gene segment is
  • the transgene contain at least one ⁇ gene segment and at least one other constant region gene segment, more preferably a ⁇ gene segment, and most preferably ⁇ 3 or ⁇ 1.
  • constant region gene segments may also be used such as those which encode for the production of IgD, IgA and IgE.
  • transgenes wherein the order of occurrence of heavy chain C H genes will be different from the naturally-occurring spatial order found in the germline of the species serving as the donor of the C H genes.
  • C H genes from more than one individual of a species (e.g., allogeneic C H genes) and incorporate said genes in the
  • the resultant transgenic nonhuman animal may then, in some embodiments, make antibodies of various classes including all of the allotypes represented in the species from which the transgene C H genes were obtained.
  • C H gene combinations will produce a transgenic nonhuman animal which may produce antibodies of various classes corresponding to C H genes from various
  • Transgenic nonhuman animals containing interspecies C H transgenes may serve as the source of B-cells for
  • the heavy chain J region segments in the human comprise six functional J segments and three pseudo genes clustered in a 3 kb stretch of DNA. Given its relatively compact size and the ability to isolate these segments
  • J region gene segments be used in the mini-locus construct. Since this fragment spans the region between the ⁇ and ⁇ genes, it is likely to contain all of the 3' cis-linked regulatory elements required for ⁇ expression. Furthermore, because this fragment includes the entire J region, it contains the heavy chain enhancer and the ⁇ switch region (Mills et al., Nature 306:809 (1983); Yancopoulos and Alt, Ann. Rev. Immunol. 4:339-368 (1986), which are incorporated herein by reference).
  • the human D region consists of 4 or 5 homologous 9 kb subregions, linked in tandem (Siebenlist, et al. (1981), Nature, 294, 631-635). Each subregion contains up to 10 individual D segments. Some of these segments have been mapped- and are shown in Fig. 4.
  • Two different strategies are used to generate a mini-locus D region. The first strategy involves using only those D segments located in a short contiguous stretch of DNA that includes one or two of the repeated D subregions. A candidate is a single 15 kb fragment that contains 12 individual D segments. This piece of DNA consists of 2 contiguous EcoRI fragments and has been
  • D segments should be sufficient for a primary repertoire.
  • an alternative strategy is to ligate together several non-contiguous D-segment containing fragments, to produce a smaller piece of DNA with a greater number of segments. Additional D-segment genes can be identified, for example, by the presence of characteristic flanking nonamer and heptamer sequences, supra, and by reference to the
  • At least one, and preferably more than one V gene segment is used to construct the heavy chain minilocus
  • V segments, D segments, J segments, and C genes, with or without flanking sequences can be isolated as described in PCT Publication No. WO 92/03918, published March 19, 1992.
  • a minilocus light chain transgene may be similarly constructed from the human ⁇ or ⁇ immunoglobulin locus.
  • an immunoglobulin heavy chain minilocus transgene construct e.g., of about 75 kb, encoding V, D, J and constant region sequences can be formed from a plurality of DNA fragments, with each sequence being substantially homologous to human gene sequences.
  • the sequences are operably linked to transcription regulatory sequences and are capable of undergoing rearrangement.
  • constant region sequences e.g., ⁇ and ⁇
  • switch regions switch recombination also occurs.
  • An exemplary light chain transgene construct can be formed similarly from a plurality of DNA fragments, substantially homologous to human DNA and capable of undergoing
  • transgene constructs that are intended to undergo class switching should include all of the cis-acting sequences necessary to regulate sterile transcripts.
  • Switch regions and upstream promoters and regulatory sequences are preferred cis-acting sequences that are included in transgene constructs capable of isotype switching.
  • switch regions can be linked upstream of (and adjacent to) C H genes that do not naturally occur next to the particular switch region.
  • a human ⁇ 1 switch region may be linked upstream from a human ⁇ 2 C H gene, or a murine ⁇ 1 switch may be linked to a human C H gene.
  • An alternative method for obtaining ⁇ on-classical isotype switching (e.g., (S-associated deletion) in transgenic mice involves the inclusion of the 400 bp direct repeat sequences ( ⁇ and e ⁇ ) that flank the human ⁇ gene (Yasui et al., Eur. J. Immunol. 19:1399 (1989)).
  • Heavy chain transgenes can be
  • V H is a heavy chain variable region gene segment
  • D is a heavy chain D (diversity) region gene segment
  • J H is a heavy chain J (joining) region gene segment
  • S D is a donor region segment capable of participating in a recombination event with the S a acceptor region
  • C 1 is a heavy chain constant region gene segment encoding an isotype utilized in for B cell development (e.g., ⁇ or ⁇ ) ,
  • T is a cis-acting transcriptional regulatory region
  • S A is an acceptor region segment capable of participating in a recombination event with selected S D donor region segments, such that isotype switching occurs
  • C 2 is a heavy chain constant region gene segment encoding an isotype other than ⁇ (e.g., ⁇ 1 , ⁇ 2 , ⁇ 3 , ⁇ 4 , ⁇ 1 , ⁇ 2 , ⁇ ).
  • V H , D, J H , S D , C 1 , T, S A , and C Z segments may be selected from various species, preferably mammalian species, and more preferably from human and murine germline DNA.
  • V H segments may be selected from various species, but are preferably selected from V H segments that occur naturally in the human germline, such as V H251 . Typically about 2 V H gene segments are included, preferably about 4 V H segments are included, and most preferably at least about 10 V H segments are included.
  • At least one D segment is typically included, although at least 10 D segments are preferably included, and some embodiments include more than ten D segments. Some preferred embodiments include human D segments.
  • At least one J H segment is incorporated in the transgene, although it is preferable to include about six J H segments, and some preferred embodiments include more than about six J H segments. Some preferred embodiments include human J H segments, and further preferred embodiments include six human J H segments and no nonhuman J H segments.
  • S D segments are donor regions capable of
  • S D and S A are switch. regions such as S ⁇ , s ⁇ 1 , S ⁇ 2 . S ⁇ 3 , S ⁇ 4 , S ⁇ , S ⁇ 2 , and S ⁇ .
  • the switch regions are murine or human, more preferably S D is a human or murine S and S A is a human or murine S ⁇ 1 .
  • S D and S A are preferably the 400 basepair direct repeat sequences that flank the human ⁇ gene.
  • C 1 segments are typically ⁇ or ⁇ genes, preferably a ⁇ gene, and more preferably a human or murine ⁇ gene.
  • T segments typically include S' flanking sequences that are adjacent to naturally occurring (i.e., germline) switch regions. T segments typically at least about at least 50 nucleotides in length, preferably about at least 200 nucleotides in length, and more preferably at least 500-1000 nucleotides in length. Preferably T segments are 5' flanking sequences that occur immediately upstream of human or murine switch regions in a germline configuration. It is also evident to those of skill in the art that T segments may comprise cis-acting transcriptional regulatory sequences that do not occur naturally in an animal germline (e.g., viral enhancers and promoters such as those found in SV40,
  • adenovirus and other viruses that infect eukaryotic cells.
  • C 2 segments are typically a ⁇ 1 , ⁇ 2 , ⁇ 3 , ⁇ 4 , ⁇ 1 , ⁇ 2 , or ⁇ C H gene, preferably a human C H gene of these isotypes, and more preferably a human ⁇ 1 or ⁇ 3 gene.
  • Murine ⁇ 2a and ⁇ 2b may also be used, as may downstream (i.e., switched) isotype genes form various species.
  • the total length of the transgene will be typically 150 kilo basepairs or less.
  • the transgene will be other than a native heavy chain Ig locus.
  • deletion of unnecessary regions or substitutions with corresponding regions from other species will be present.
  • transgenic nonhuman animal The occurrence of isotype switching in a transgenic nonhuman animal may be identified by any method known to those in the art. Preferred embodiments include the following, employed either singly or in combination:
  • detection of mRNA transcripts that contain a sequence homologous to at least one transgene downstream C H gene other than ⁇ and an adjacent sequence homologous to a transgene V H - D H -J H rearranged gene; such detection may be by Northern hybridization, S 1 nuclease protection assays, PCR
  • detection in DNA from B-cells of the transgenic animal or in genomic DNA from hybridoma cells, of DNA rearrangements consistent with the occurrence of isotype switching in the transgene, such detection may be accomplished by Southern blot hybridization, PCR amplification, genomic cloning, or other method; or
  • each transgenic line may represent a
  • transgenes are typically integrated into host chromosomal DNA, most usually into germline DNA and propagated by subsequent breeding of germline transgenic breeding stock animals. However, other vectors and transgenic methods known in the present art or subsequently developed may be substituted as appropriate and as desired by a
  • Endogenous Immunoglobulin Loci The expression of successfully rearranged immunoglobulin heavy and light transgenes is expected to have a dominant effect by suppressing the rearrangement of the endogenous immunoglobulin genes in the transgenic nonhuman animal.
  • Another way to generate a nonhuman that is devoid of endogenous antibodies is by mutating the endogenous immunoglobulin loci. Using embryonic stem cell technology and homologous recombination, the endogenous immunoglobulin repertoire can be readily eliminated. The following describes the functional description of the mouse immunoglobulin loci.
  • the vectors and methods disclosed, however, can be readily adapted for use in other non-human animals.
  • this technology involves the inactivation of a gene, by homologous recombination, in a pluripotent cell line that is capable of differentiating into germ cell tissue.
  • a DNA construct that contains an altered, copy of a mouse immunoglobulin gene is introduced into the nuclei of embryonic stem cells. In a portion of the cells, the introduced DNA recombines with the endogenous copy of the mouse gene,
  • the mouse ⁇ locus contributes to only 5% of the immunoglobulins, inactivation of the heavy chain and/or ⁇ -light chain loci is sufficient. There are three ways to disrupt each of these loci, deletion of the J region, deletion of the J-C intron enhancer, and disruption of constant region coding sequences by the introduction of a stop codon. The last option is the most straightforward, in terms of DNA construct design. Elimination of the ⁇ gene disrupts B-cell maturation thereby preventing class switching to any of the functional heavy chain segments. The strategy for knocking out these loci is outlined below.
  • neomycin resistance gene from the plasmid pMCIneo is inserted into the coding region of the target gene.
  • the pMCIneo insert uses a hybrid viral promoter/enhancer sequence to drive neo expression. This promoter is active in embryonic stem cells. Therefore, neo can be used as a selectable marker for integration of the knock-out construct.
  • the HSV thymidine kinase (tk) gene is added to the end of the construct as a negative selection marker against random insertion events (Zijlstra, et al., supra.).
  • a preferred strategy for disrupting the heavy chain locus is the elimination of the J region. This region is fairly compact in the mouse, spanning only 1.3 kb.
  • the heavy-chain locus is knocked out by disrupting the coding region of the ⁇ gene.
  • This approach involves the same 15 kb Kpnl fragment used in the previous approach.
  • the 1.1 kb insert from pMCIneo is inserted at a unique BamHI site in exon II, and the HSV tk gene added to the 3' Kpnl end. Double crossover events on either side of the neo insert, that eliminate the tk gene, are then selected for. These are detected from pools of selected clones by PCR amplification.
  • One of the PCR primers is derived from neo sequences and the other from mouse sequences outside of the targeting vector. The functional disruption of the mouse immunoglobulin loci is presented in the Examples.
  • an alternative method for preventing the expression of an endogenous Ig locus is suppression.
  • Suppression of endogenous Ig genes may be accomplished with antisense RNA produced from one or more integrated transgenes, by antisense oligonucleotides, and/or by administration of antisera
  • Antisense RNA transgenes can be employed to
  • Antisense polynucleotides are polynucleotides that: (1) are complementary to all or part of a reference sequence, such as a sequence of an endogenous Ig C H or C L region, and (2) which specifically hybridize to a
  • complementary target sequence such as a chromosomal gene locus- or a Ig mRNA.
  • polynucleotides may include nucleotide substitutions,
  • Complementary antisense polynucleotides include soluble antisense RNA or DNA oligonucleotides which can hybridize specifically to
  • An antisense sequence is a
  • polynucleotide sequence that is complementary to at least one immunoglobulin gene sequence of at least about 15 contiguous nucleotides in length, typically at least 20 to 30 nucleotides in length, and preferably more than about 30 nucleotides in length.
  • antisense sequences may have substitutions, additions, or deletions as compared to the complementary immunoglobulin gene sequence, so long as
  • an antisense sequence is complementary to an endogenous immunoglobulin gene sequence that encodes, or has the potential to encode after DNA
  • sense sequences corresponding to an immunoglobulin gene sequence may function to suppress expression, particularly by interfering with transcription.
  • antisense polynucleotides therefore inhibit production of the encoded polypeptide (s).
  • antisense polynucleotides that inhibit transcription and/or translation of one or more endogenous Ig loci can alter the capacity and/or specificity of a non-human animal to produce immunoglobulin chains encoded by endogenous Ig loci.
  • Antisense polynucleotides may be produced from a heterologous expression cassette in a transfectant cell or transgenic cell, such as a transgenic pluripotent
  • the antisense polynucleotides may comprise soluble oligonucleotides that are administered to the external milieu, either in culture medium in vitro or in the circulatory system or interstitial fluid in vivo. Soluble antisense polynucleotides present in the external milieu have been shown to gain access to the
  • the antisense polynucleotides comprise methylphosphonate moieties, alternatively phosphorothiolates or O-methylribonucleotides may be used, and chimeric
  • oligonucleotides may also be used (Dagle et al. (1990) Nucleic Acids Res. 18: 4751). For some applications, antisense
  • oligonucleotides may comprise polyamide nucleic acids (Nielsen et al. (1991) Science 254: 1497). For general methods
  • Antisense polynucleotides complementary to one or more sequences are employed to inhibit transcription, RNA processing, and/or translation of the cognate mRNA species andthereby effect a reduction in the amount of the respective encoded polypeptide.
  • Such antisense polynucleotides can provide a therapeutic function by inhibiting the formation of one or more endogenous Ig chains in vivo.
  • the antisense polynucleotides of this invention are selected so as to hybridize preferentially to endogenous Ig sequences at physiological conditions in vivo. Most typically, the
  • selected antisense polynucleotides will not appreciably hybridize to heterologous Ig sequences encoded by a heavy or light chain transgene of the invention (i.e., the antisense oligonucleotides will not inhibit transgene Ig expression by more than about 25 to 35 percent).
  • Partial or complete suppression of endogenous Ig chain expression can be produced by injecting mice with antisera against one or more endogenous Ig chains (Weiss et al. (1984) Proc. ⁇ atl. Acad. Sci. (U.S.A.) 81 211, which is incorporated herein by reference).
  • Antisera are selected so as to react specifically with one or more endogenous Ig chains but to have minimal or no cross-reactivity with heterologous Ig chains encoded by an Ig transgene of the invention.
  • administration of selected antisera according to a schedule as typified by that of Weiss et al. op.cit. will suppress
  • nucleic acids the term "substantial homology” indicates" that two nucleic acids, or de gnated sequences thereof, when optimally aligned and compared, are identical, with appropriate nucleotide insertions or deletions, in at least about 80% of the nucleotides, usually at least about 90% to 95%, and more preferably at least about 98 to 99.5% of the nucleotides. Alternatively, substantial homology exists when the segments will hybridize under selective hybridization conditions, to the complement of the strand.
  • the nucleic acids may be present in whole cell ⁇ , in a cell lysate, or in a partially purified or substantially pure form.
  • a nucleic acid is "isolated” or “rendered substantially pure” when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCl banding, column chromatography, agarose gel electrophoresis and others well known in the art. See, F. Ausubel, et al., ed. Current Protocols in Molecular Biology, Greene Publishing and Wiley- Interscience, New York (1987).
  • DNA sequences substantially identical to a native sequence (except for modified restriction sites and the like), from either cDNA, genomic or mixtures may be mutated, thereof in accordance with standard techniques to provide gene sequences.
  • these mutations may affect amino acid sequence as desired.
  • DNA sequences substantially identical to a native sequence (except for modified restriction sites and the like), from either cDNA, genomic or mixtures may be mutated, thereof in accordance with standard techniques to provide gene sequences.
  • these mutations may affect amino acid sequence as desired.
  • DNA sequences substantially identical to a native sequence (except for modified restriction sites and the like), from either cDNA, genomic or mixtures may be mutated, thereof in accordance with standard techniques to provide gene sequences.
  • these mutations may affect amino acid sequence as desired.
  • DNA sequences substantially identical to a native sequence (except for modified restriction sites and the like), from either cDNA, genomic or mixtures may be mutated, thereof in accordance with standard techniques to provide gene sequences.
  • these mutations may affect amino acid sequence as desired.
  • a nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence.
  • a promoter or enhancer is operably linked to a coding sequence if it affects the
  • operably linked means that the DNA sequences being linked are contiguous and, where necessary to join two protein coding regions, contiguous and in reading frame.
  • operably linked indicates that the sequences are capable of effecting switch recombination.
  • a preferred embodiment of the invention is an animal containing at least one, typically 2-10, and sometimes 25-50 or more copies of the transgene described in Example 12 (e.g., pHC1 or pHC2) bred with an animal containing a single copy of a light chain transgene described in Examples 5, 6, 8, or 14, and the offspring bred with the J H deleted animal described in Example 10. Animals are bred to homozygosity for each of these three traits.
  • Such animals have the following genotype: a single copy (per haploid set of chromosomes) of a human heavy chain unrearranged mini-locus (described in Example 12), a single copy (per haploid set of chromosomes) of a rearranged human ⁇ light chain construct (described in Example 14), and a deletion at each endogenous mouse heavy chain locus that removes all of the functional J H segments (described in
  • Example 10 Such animals are bred with mice that are
  • B cells will be monospecific with regards to human or mouse heavy chains because both endogenous mouse heavy chain gene copies are nonfunctional by virtue of the deletion spanning the J H region introduced as described in Example 9 and 12. Furthermore, a substantial fraction of the B cells will be monospecific with regards to the human or mouse light chains because expression of the single copy of the rearranged human ⁇ light chain gene will allelically and isotypically exclude the rearrangement of the endogenous mouse ⁇ and ⁇ chain genes in a significant fraction of B-cells.
  • the transgenic mouse of the preferred embodiment will exhibit immunoglobulin production with a significant repertoire, ideally substantially similar to that of a native mouse.
  • the total immunoglobulin levels will range from about 0.1 to 10 mg/ml of serum,
  • the adult mouse ratio of serum IgG to IgM is preferably about 10:1.
  • the IgG to IgM ratio will be much lower in the
  • spleen and lymph node B cells express exclusively human IgG protein.
  • the repertoire will ideally approximate that shown in a non-transgenic mouse, usually at least about 10% as high, preferably 25 to 50% or more.
  • immunoglobulins ideally IgG
  • 10 4 to 10 6 or more will be produced, depending primarily on the number of different V, J and D regions introduced into the mouse genome.
  • These immunoglobulins will typically recognize about one-half or more of highly antigenic proteins,
  • immunoglobulins will exhibit an affinity for preselected antigens of at least about 10 7 M -1 , preferably 10 8 M -1 to 10 9 M -1 or greater.
  • transgenic animal prior to rearrangement of a transgene containing various heavy or light chain gene segments, such gene segments may be readily identified, e.g. by hybridization or DNA sequencing, as being from a species of organism other than the transgenic animal.
  • transgenic animal of the invention Although the foregoing describes a preferred embodiment of the transgenic animal of the invention, other embodiments are defined by the disclosure herein and more particularly by the transgenes described in the Examples.
  • transgenic animal Four categories of transgenic animal may be defined:
  • Transgenic animals containing an unrearranged heavy and unrearranged light immunoglobulin transgene III Transgenic animal containing rearranged heavy and an unrearranged light immunoglobulin transgene, and IV.
  • the preferred order of preference is as follows II > I > III > IV where the endogenous light chain genes (or at least the ⁇ gene) have been knocked out by homologous recombination (or other method) and I > II > III >IV where the endogenous light chain genes have not been knocked out and must be dominated by allelic exclusion.
  • Transgenic mice are derived according to Hogan, et al., "Manipulating the Mouse Embryo: A Laboratory Manual", Cold Spring Harbor Laboratory, which is incorporated herein by reference.
  • Embryonic stem cells are manipulated according to published procedures (Teratocarcinomas and embryonic stem cells: a practical approach, E.J. Robertson, ed., IRL Press, Washington, D.C., 1987; Zjilstra et al., Nature 342:435-438 (1989); and Schwartzberg et al., Science 246:799-803 (1989), each of which is incorporated herein by reference).
  • Oligonucleotides are synthesized on an Applied Bio Systems oligonucleotide synthesizer according to
  • Hybridoma cells and antibodies are manipulated according to "Antibodies: A Laboratory Manual”, Ed Harlow and David Lane, Cold Spring Harbor Laboratory (1988), which is incorporated herein by reference.
  • the isolated nuclei (or PBS washed human spermatocytes) are embedded in a low melting point agarose matrix and lysed with EDTA and proteinase ⁇ to expose high molecular weight DNA, which is then digested in the agarose with the restriction enzyme NotI as described by M. Finney in Current Protocols in Molecular Biology (F. Ausubel, et al., eds. John Wiley & Sons, Supp. 4, 1988, Section 2.5.1).
  • the NotI digested DNA is then fractionated by pulsed field gel electrophoresis as described by Anand et al.,
  • Plasmid pYACNN is prepared by digestion of pYAC-4 Neo (Cook et al., Nucleic Acids Res. 16: 11817 (1988)) with EcoRI and ligation in the presence of the oligonucleotide 5' - AAT TGC GGC CGC - 3'.
  • a 450 kb Xhol to NotI fragment that includes all of C ⁇ , the 3' enhancer, all J segments, and at least five different V segments is isolated and microinjected into the nucleus of single cell embryos as described in Example 1.
  • a 750 kb Mlul to NotI fragment that includes all of the above plus at least 20 more V segments is isolated as described in Example 1 and digested with BssHII to produce a fragment of about 400 kb.
  • the 450 kb Xhol to NotI fragment plus the approximately 400 kb Mlul to BssHII fragment have sequence overlap defined by the BssHII and Xhol restriction sites.
  • pBR322 is digested with EcoRI and StyI and ligated with the following oligonucleotides to generate pGP1 which contains a 147 base pair insert containing the restriction sites shown in Fig. 8. The general overlapping of these oligos is also shown in Fig. 9.
  • the oligonucleotides are:
  • AAA AGC CCG CTC ATT AGG CGG GCT - 3'
  • This plasmid contains a large polylinker flanked by rare cutting NotI sites for building large inserts that can be isolated from vector sequences for microinjection.
  • the plasmid is based on pBR322 which is relatively low copy compared to the pUC based plasmids (pGP1 retains the pBR322 copy number control region near the origin of replication). Low copy number reduces the potential toxicity of insert sequences.
  • pGP1 contains a strong transcription terminator sequence derived from trpA (Christie et al., Proc. Natl. Acad. Sci. USA 78:4180 (1981)) inserted between the ampicillin resistance gene and the polylinker. This further reduces the toxicity associated with certain inserts by preventing readthrough transcription coming from the
  • ampicillin promoters are ampicillin promoters.
  • Plasmid pGP2 is derived from pGP1 to introduce an additional restriction site (Sfil) in the polylinker.
  • pGP1 is digested with Mlul and Spel to cut the recognition sequences in the polylinker portion of the plasmid.
  • the following adapter oligonucleotides are ligated to the thus digested pGP1 to form pGP2.
  • a 3' pGP2 is identical to pGP1 except that it contains an additional Sfi I site located between the Mlul and Spel sites. This allows inserts to be completely excised with Sfil as well as with NotI.
  • the rat IGH 3' enhancer sequence is PCR amplified by using the following oligonucleotides: 5' CAG GAT CCA GAT ATC AGT ACC TGA AAC AGG GCT TGC 3'
  • the thus formed double stranded DNA encoding the 3' enhancer is cut with BamHI and SphI and clone into BamHI/SphI cut pGP2 to yield pRE3 (rat enhancer 3').
  • pMUM is 4 kb EcoRI/Hindlll fragment isolated from human genomic DNA library with oligonucleotide:
  • pGP1 is digested with BamHI and Bglll followed by treatment with calf intestinal alkaline phosphatase.
  • Fragments (a) and (b) from Fig. 9 are cloned in the digested pGP1.
  • a clone is then isolated which is oriented such that 5' BamHI site is destroyed by BamHI/Bgl fusion. It is identified as pMU (see Fig. 10).
  • pMU is digested with BamHI and fragment (c) from Fig. 9 is inserted.
  • the resultant plasmid pHIG1 (Fig. 10) contains an 18 kb insert encoding J and C ⁇ segments.
  • pGP1 is digested with BamHI and Hindlll is followed by treatment with calf intestinal alkaline phosphatase (Fig. 14).
  • the so treated fragment (b) of Fig. 14 and fragment (c) of Fig. 14 are cloned into the BamHI/Hindlll cut pGP1.
  • Proper orientation of fragment (c) is checked by Hindlll digestion to form pCON1 containing a 12 kb insert encoding the C ⁇ region.
  • pHIGl contains J segments, switch and ⁇ sequences in its 18 kb insert with an Sfil 3' site and a Spel 5' site in a polylinker flanked by NotI sites, will be used for rearranged VDJ segments.
  • pCON1 is identical except that it lacks the J region and contains only a 12 kb insert. The use of pCON1 in the construction of fragment containing rearranged VDJ segments will be described hereinafter.
  • An intronic sequence is a nucleotide sequence of at least 15 contiguous nucleotides that occurs in an intron of a specified gene.
  • Phage clones containing the ⁇ -1 region are identified and isolated "sing the following oligonucleotide which is specific for the third exon of ⁇ -1 (CH3).
  • a 7.7 kb Hindlll to Bglll fragment (fragment (a) in Fig. 11) is cloned into Hindlll/Bglll cut pRE3 to form pREGl.
  • the upstream 5.3 kb Hindlll fragment (fragment (b) in Fig. 11) is cloned into Hindlll digested pREGl to form pREG2. Correct orientation is confirmed by BamHI/Spel digestion.
  • the previously described plasmid pHIGl contains human J segments and the C ⁇ constant region exons.
  • pHIG1 was digested with Sfil (Fig. 10).
  • the plasmid pREG2 was also digested with Sfil to produce a 13.5 kb insert containing human C ⁇ exons and the rat 3' enhancer sequence.
  • sequences were combined to produce the plasmid pHIG3' (Fig. 12) containing the human J segments, the human C ⁇ constant region, the human C ⁇ 1 constant region and the rat 3' enhancer contained on a 31.5 kb insert.
  • a second plasmid encoding human C ⁇ and human C ⁇ 1 without J segments is constructed by digesting pCON1 with Sfil and combining that with the Sfil fragment containing the human C ⁇ region and the rat 3' enhancer by digesting pREG2 with Sfil.
  • the resultant plasmid, pCON (Fig. 12) contains a 26 kb NotI/Spel insert containing human C ⁇ , human ⁇ 1 and the rat 3' enhancer sequence.
  • Fig. 13 Phage clones from the human genomic library containing D segments are identified and isolated using probes specific for diversity region sequences (Ichihara et al., EMBO J. 7:4141-4150 (1988)). The following
  • oligonucleotides are used:
  • DXP1 5' - TGG TAT TAC TAT GGT TCG GGG AGT TAT TAT
  • DXP4 5' - GCC TGA AAT GGA GCC TCA GGG CAC AGT GGG
  • CAC GGA CAC TGT - 3' DN4 5' - GCA GGG AGG ACA TGT TTA GGA TCT GAG GCC
  • a 5.2 kb Xhol fragment (fragment (b) in Fig. 13) containing DLR1, DXP1, DXP'1, and DA1 is isolated from a phage clone identified with oligo DXP1.
  • a 3.2 kb Xbal fragment (fragment (c) in Fig. 13) containing DXP4, DA4 and DK4 is isolated from a phage clone identified with oligo DXP4.
  • This plasmid contains diversity segments cloned into the polylinker with a unique 5' Sfil site and unique 3' Spel site. The entire polylinker is flanked by NotI sites.
  • a restriction map of the unrearranged V segment is determined to identify unique restriction sites which provide upon digestion a DNA fragment having a length approximately 2 kb containing the unrearranged V segment together with 5' and 3' flanking sequences.
  • the 5' prime sequences will include promoter and other regulatory sequences whereas the 3'
  • flanking sequence provides recombination sequences necessary for V-DJ joining. This approximately 3.0 kb V segment insert is cloned into the polylinker of pGB2 to form pVH1.
  • pVHl is digested with Sfil and the resultant fragment is cloned into the Sfil site of pHIG2 to form a
  • pHIG5 contains D segments only, the resultant pHIG5' plasmid contains a single V segment together with D segments.
  • the size of the insert contained in pHIG5 is 10.6 kb plus the size of the V segment insert.
  • pHIG5 The insert from pHIG5 is excised by digestion with NotI and Spel and isolated.
  • pHIG3' which contains J, C ⁇ and C ⁇ 1 segments is digested with Spel and NotI and the 3' kb fragment containing such sequences and the rat 3' enhancer sequence is isolated. These two fragments are combined and ligated into NotI digested pGP1 to produce pHIG which contains insert encoding a V segment, nine D segments, six functional J segments, C ⁇ , C ⁇ and the rat 3' enhancer.
  • the size of this insert is approximately 43 kb plus the size of the V segment insert.
  • the insert of pHIG is approximately 43 to 45 kb when a single V segment is employed. This insert size is at or near the limit of that which may be readily cloned into plasmid vectors.
  • the following describes in vivo homologous recombination of overlapping DNA fragments which upon homologous recombination within a zygote or ES cell form a transgene containing the rat 3' enhancer sequence, the human C ⁇ , the human C ⁇ 1, human J segments, human D segments and a multiplicity of human V segments.
  • a 6.3 kb BamHI/Hindlll fragment containing human J segments (see fragment (a) in Fig. 9) is cloned into Mlul/Spel digested pHIG5' using the following adapters: 5' GAT CCA AGC AGT 3'
  • the resultant is plasmid designated pHIG5'O (overlap).
  • the insert contained in this plasmid contains human V, D and J segments. When the single V segment from pVHl is used, the size of this insert is approximately 17 kb plus 2 kb.
  • This insert is isolated and combined with the insert from pHIG3' which contains the human J, C ⁇ , ⁇ 1 and rat 3' enhancer sequences. Both inserts contain human J segments which provide for approximately 6.3 kb of overlap between the two DNA fragments. When coinjected into the mouse zygote, in vivo homologous recombination occurs generating a transgene equivalent to the insert contained in pHIG.
  • This approach provides for the addition of a multiplicity of V segments into the transgene formed in vivo.
  • a multiplicity of V segments contained on (1) isolated genomic DNA, (2) ligated DNA derived from genomic DNA, or (3) DNA encoding a synthetic V segment repertoire is cloned into pHIG2 at the Sfil site to generate pHIG5' V N .
  • the J segments fragment (a) of Fig. 9 is then cloned into pHIG5' V N and the insert isolated.
  • This insert now contains a multiplicity of V segments and J segments which overlap with the J segments contained on the insert isolated from pHIG3'.
  • mouse heavy chain enhancer is isolated on the Xbal to EcoRI 678 bp fragment (Banerji et al., Cell 33:729-740 (1983)) from phage clones using oligo: 5' GAA TGG GAG TGA GGC TCT CTC ATA CCC
  • the ⁇ construct contains at least one human V ⁇ segment, all five human J ⁇ segments, the human J-C ⁇ enhancer, human ⁇ constant region exon, and, ideally, the human 3' ⁇ enhancer (Meyer et al., EMBO J. 8:1959-1964 (1989)).
  • the ⁇ enhancer in mouse is 9 kb downstream from C ⁇ . However, it is as yet unidentified in the human.
  • the construct contains a copy of the mouse heavy chain J-C ⁇ enhancers.
  • the minilocus is constructed from four component fragments:
  • this sequence is included to induce expression of the light chain construct as early as possible in B-cell development. Because the heavy chain genes are transcribed earlier than the light chain genes, this heavy chain enhancer is presumably active at an earlier stage than the intronic ⁇ enhancer); and
  • the 16 kb fraction is isolated from the Smal digested gel and the 11 kb region is similarly isolated from the gel containing DNA digested with BamHI.
  • the 11 kb BamHI fraction is cloned into ⁇ EMBL3 (Strategene, La Jolla, California) which is digested with BamHI prior to cloning.
  • the above C ⁇ specific oligonucleotide is used to probe the ⁇ EMBL3/BamHI library to identify an 11 kb clone.
  • a 5 kb Smal fragment fragment (b) in Fig. 20) is subcloned and subsequently inserted into pKapl digested with Smal.
  • Those plasmids containing the correct orientation of J segments, C ⁇ and the E ⁇ enhancer are designated pKap2.
  • V ⁇ segments are thereafter subcloned into the Mlul site of pKap2 to yield the plasmid pKapH which encodes the human V ⁇ segments, the human J ⁇ segments, the human C ⁇ segments and the human E ⁇ enhancer.
  • This insert is excised by digesting pKapH with NotI and purified by agarose gel electrophoresis. The thus purified insert is
  • the 11 kb BamHI fragment is cloned into BamHI .
  • V ⁇ segments is inserted into the polylinker between the BamHI and Spel sites in pKAPint to form pKapHV.
  • the insert of pKapHV is excised by digestion with NotI and purified.
  • the insert from pKap2 is excised by digestion with NotI and purified.
  • Each of these fragments contain regions of homology in that the fragment from pKapHV contains a 5 kb sequence of DNA that include the J ⁇ segments which is substantially homologous to the 5 kb Smal fragment contained in the insert obtained from pKap2.
  • these inserts are capable of homologously recombining when microinjected into a mouse zygote to form a transgene encoding V ⁇ , J ⁇ and C ⁇ .
  • This example describes the cloning of immunoglobulin ⁇ light chain genes from cultured cells that express an immunoglobulin of interest.
  • Such cells may contain multiple alleles of a given immunoglobulin gene.
  • a hybridoma might contain four copies of the ⁇ light chain gene, two copies from the fusion partner cell line and two copies from the original B-cell expressing the immunoglobulin of interest. Of these four copies, only one encodes the
  • immunoglobulin of interest despite the fact that several of them may be rearranged.
  • the procedure described in this example allows for the selective cloning of the expressed copy of the ⁇ light chain.
  • RNA is then used for the isolation of polyA+ RNA.
  • single-stranded cDNA is then purified and used as template for second strand synthesis (catalyzed by the enzyme DNA
  • the double stranded cDNA is isolated and used for determining the nucleotide sequence of the 5' end of the mRNAs encoding the heavy and light chains of the expressed
  • the double stranded cDNA described in part A is denatured and used as a template for a third round of DNA synthesis using the following oligonucleotide primer: 5' - GTA CGC CAT ATC AGC TGG ATG AAG TCA TCA GAT
  • This primer contains sequences specific for the constant portion of the ⁇ light chain message (TCA TCA GAT GGC GGG AAG ATG AAG ACA GAT GGT GCA) as well as unique sequences that can be used as a primer for the PCR amplification of the newly synthesized DNA strand (GTA CGC CAT ATC AGC TGG ATG AAG).
  • the sequence is amplified by PCR using the following two oligonucleotide primers: 5' - GAG GTA CAC TGA CAT ACT GGC ATG -3'
  • the PCR amplified sequence is then purified by gel electrophoresis and used as template for dideoxy sequencing reactions using the following oligonucleotide as a primer: 5' - GAG GTA CAC TGA CAT ACT GGC ATG -3'
  • the first 42 nucleotides of sequence will then be used to synthesize a unique probe for isolating the gene from which immunoglobulin message was transcribed.
  • This synthetic 42 nucleotide segment of DNA will be referred to below as o-kappa.
  • DNA from the Ig expressing cell line is then cut with Smal and second enzyme (or BamHI or Kpnl if there is Smal site inside V segment). Any resulting non-blunted ends are treated with the enzyme T4 DNA polymerase to give blunt ended DNA molecules. Then add restriction site encoding linkers (BamHI, EcoRI or Xhol depending on what site does not exist in fragment) and cut with the corresponding linker enzyme to give DNA fragments with BamHI, EcoRI or Xhol ends. The DNA is then size fractionated by agarose gel electrophoresis, and the fraction including the DNA fragment covering the expressed V segment is cloned into lambda EMBL3 or Lambda FIX (Stratagene, La Jolla, California).
  • V segment containing clones are isolated using the unique probe o-kappa.
  • DNA is isolated from positive clones and subcloned into the polylinker of pKapl. The resulting clone is called pRKL.
  • This example describes the cloning of immunoglobulin heavy chain ⁇ genes from cultured cells of expressed and immunoglobulin of interest. The procedure described in this example allows for the selective cloning of the expressed copy of a ⁇ heavy chain gene.
  • Double-stranded cDNA is prepared and isolated as described herein before.
  • the double-stranded cDNA is
  • This primer contains sequences specific for the constant portion of the ⁇ heavy chain message (ACA GGA GAC GAG GGG GAA AAG GGT TGG GGC GGA TGC) as well as unique sequences that can be used as a primer for the PCR amplification of the newly synthesized DNA strand (GTA CGC CAT ATC AGC TGG ATG AAG).
  • the sequence is amplified by PCR using the following two oligonucleotide primers:
  • PCR amplified sequence is then purified by gel electrophoresis and used as template for dideoxy sequencing reactions using the following oligonucleotide as a primer:
  • Mlul is a rare cutting enzyme that cleaves between the J segment and mu CH1
  • Mlul is a rare cutting enzyme that cleaves between the J segment and mu CH1
  • restriction endonuclease site is identified upstream of the rearranged V segment.
  • DNA from the Ig expressing cell line is then cut with Mlul and second enzyme.
  • Mlul or Spel adapter linkers are then ligated onto the ends and cut to convert the upstream site to Mlul or Spel.
  • the DNA is then size fractionated by agarose gel electrophoresis, and the fraction including the DNA fragment covering the expressed V segment is cloned directly into the plasmid pGP1.
  • V segment containing clones are isolated using the unique probe o-mu, and the insert is subcloned into Mlul or Mlul/Spel cut plasmid pCON2. The resulting plasmid is called pRMGH.
  • a human genomic DNA phage library was screened with kappa light chain specific oligonucleotide probes and isolated clones spanning the J ⁇ -C region.
  • a 5.7 kb Clal/Xhol fragment containing J ⁇ 1 together with a 13 kb Xhol fragment containing J ⁇ 2-5 and C ⁇ into pGP1d was cloned and used to create the plasmid pKcor. This plasmid contains J ⁇ 1-5, the kappa
  • V ⁇ light chain specific oligonucleotide probes were screened with V ⁇ light chain specific oligonucleotide probes and isolated clones containing human V ⁇ segments. Functional V segments were identified by DNA sequence analysis. These clones contain TATA boxes, open reading frames encoding leader and variable peptides (including 2 cysteine residues), splice sequences, and recombination heptamer-12 bp spacer-nonamer sequences. Three of the clones were mapped and sequenced.
  • Two of the clones, 65.5 and 65.8 appear to be functional, they contain TATA boxes, open reading frames encoding leader and variable peptides (including 2 cysteine residues), splice sequences, and recombination heptamer-12 bp spacer-nonamer sequences.
  • the third clone, 65.4 appears to encode a V ⁇ I pseudogene as it contains a non-canonical recombination heptamer.
  • Vk 65-8 which encodes a Vklll family gene, was used to build a light chain minilocus construct.
  • the kappa light chain minilocus transgene pKC1 (Fig. 32) was generated by inserting a 7.5 kb Xhol/Sall fragment containing V ⁇ 65.8 into the 5' Xhol site of pKcor.
  • the transgene insert was isolated by digestion with NotI prior to injection.
  • the purified insert was microinjected into the pronuclei of fertilized (C57BL/6 x CBA) F2 mouse embryos and transferred the surviving embryos into pseudopregnant females as described by Hogan et al. (in Methods of Manipulating the Mouse Embryo, 1986, Cold Spring Harbor Laboratory, New York). Mice that developed from injected embryos were analyzed for the presence of transgene sequences by Southern blot analysis of tail DNA. Transgene copy number was estimated by band intensity relative to control standards containing known quantities of cloned DNA.
  • Serum was isolated from these animals and assayed for the presence of transgene encoded human Ig kappa protein by ELISA as described by Harlow and Lane (in Antibodies: A Laboratory Manual, 1988, Cold Spring Harbor Laboratory, New York).
  • Microtiter plate wells were coated with mouse monoclonal antibodies specific for human Ig kappa (clone 6E1, #0173 , AMAC, Inc. , Westbrook, ME) , human IgM (Clone AF6, #0285, AMAC, Inc., Westbrook, ME) and human IgG1 (clone JL512, #0280, AMAC, Inc., Westbrook, ME).
  • Serum samples were serially diluted into the wells and the presence of specific immunoglobulins detected with affinity isolated alkaline phosphatase conjugated goat anti-human Ig
  • Fig. 35 shows the results of an ELISA assay of serum from 8 mice (I.D. #676, 674, 673, 670, 666, 665, 664, and 496). The first seven of these mice developed from embryos that were injected with the pKC1 transgene insert and the eighth mouse is derived from a mouse generated by
  • the kappa light chain minilocus transgene pKC2 was generated by inserting an 8 kb Xhol/Sall fragment containing V ⁇ 65.5 into the 5' Xhol site of pKC1. The resulting
  • transgene insert which contains two V ⁇ segments, was isolated prior to microinjection by digestion with NotI.
  • This construct is identical to pKCI except that it includes 1.2 kb of additional sequence 5' of J ⁇ and is missing 4.5 kb of sequence 3' of V ⁇ 65.8. In additional it contains a 0.9 kb Xbal fragment containing the mouse heavy chain J-m intronic enhancer (Banerji et al., Cell 33:729-740 (1983)) together with a 1.4 kb Mlul Hindlll fragment containing the human heavy chain J-m intronic enhancer (Hayday et al., Nature 307:334-340 (1984)) inserted downstream. This construct tests the feasibility of initiating early rearrangement of the light chain minilocus to effect allelic and isotypic exclusion.
  • enhancers i.e., the mouse or rat 3' kappa or heavy chain enhancer (Meyer and Neuberger, EMBO J. 8:1959-1964 (1989); Petterson et al. Nature 344:165-168 (1990), which are
  • a kappa light chain expression cassette was designed to reconstruct functionally rearranged light chain genes that have been amplified by PCR from human B-cell DNA.
  • the scheme is outlined in Fig. 33.
  • PCR amplified light chain genes are cloned into the vector pK5nx that includes 3.7 kb of 5' flanking sequences isolated from the kappa light chain gene 65.5.
  • the VJ segment fused to the 5' transcriptional
  • sequences are then cloned into the unique Xhol site of the vector pK31s that includes J ⁇ 2-4, the J ⁇ intronic enhancer, C ⁇ , and 9 kb of downstream sequences.
  • the resulting plasmid contains a reconstructed functionally rearranged kappa light chain transgene that can be excised with NotI for
  • the plasmids also contain unique Sall sites at the 3' end for the insertion of additional cis- acting regulatory sequences.
  • Oligonucleotide o-131 (gga ccc aga
  • Oligonucleotide o-130 (gtg caa tea att etc gag ttt gac tac aga c) is complementary to a sequence approximately 150 bp 3' of J ⁇ 1 and includes an Xhol site. These two oligonucleotides amplify a 0.7 kb DNA
  • V ⁇ III genes joined to J ⁇ 1 segments.
  • the PCR amplified DNA was digested with Ncol and Xhol and cloned individual PCR products into the plasmid pNN03.
  • the DNA sequence of 5 clones was determined and identified two with functional VJ joints (open reading frames). Additional functionally rearranged light chain clones are collected.
  • the functionally rearranged clones can be individually cloned into light chain expression
  • Transgenic mice generated with the rearranged light chain constructs can be bred with heavy chain minilocus transgenics to produce a strain of mice that express a spectrum of fully human antibodies in which all of the diversity of the primary repertoire is contributed by the heavy chain.
  • One source of light chain diversity can be from somatic mutation. Because not all light chains will be equivalent with respect to their ability to combine with a variety of different heavy chains, different strains of mice, each containing different light chain constructs can be
  • combination can result in an increased frequency of B-cells expressing fully human antibodies, and thus it can facilitate the isolation of human Ig expressing hybridomas.
  • NotI inserts of plasmids pIGM1, pHC1, pIGG1, pKC1, and pKC2 were isolated away from vector sequences by agarose gel electrophoresis. The purified inserts were microinjected into the pronuclei of fertilized (C57BL/6 x CBA) F2 mouse embryos and transferred the surviving embryos into
  • This example describes the inactivation of the mouse endogenous kappa locus by homologous recombination in
  • ES embryonic stem cells followed by introduction of the mutated gene into the mouse germ line by injection of targeted ES cells bearing an inactivated kappa allele into early mouse embryos (blastocysts).
  • the strategy is to delete J ⁇ and C ⁇ by homologous recombination with a vector containing DNA sequences
  • the plasmid pGEM7 contains the neomycin resistance gene (neo), used for drug selection of transfected ES cells, under the transcriptional control of the mouse phosphoglycerate kinase (pgk) promoter (Xbal/TaqI fragment; Adra et al., Gene 60: 65-74 (1987)) in the cloning vector pGEM- 7Zf(+).
  • the plasmid also includes a heterologous polyadenylation site for the neo gene, derived from the 3' region of the mouse pgk gene (PvulI/Hindlll fragment; Boer et al., Biochemical Genetics. 28:299-308 (1990)). This plasmid was used as the starting point for construction of the kappa targeting vector. The first step was to insert sequences homologous to the kappa locus 3' of the neo expression
  • Fig. 20a Mouse kappa chain sequences (Fig. 20a) were isolated from a genomic phage library derived from liver DNA using oligonucleotide probes specific for the C/c locus:
  • a 1.2 kb EcoRI/SphI fragment extending 5' of the J ⁇ region was also isolated from a positive phage clone.
  • An Sphl/Xbal/Bglll/EcoRI adaptor was ligated to the SphI site of this fragment, and the resulting EcoRI fragment was ligated into EcoRI digested pNEO-K3', in the same 5' to 3' orientation as the neo gene and the downstream 3' kappa sequences, to generate pNEO-K5'3' (Fig. 20c).
  • HSV Herpes Simplex Virus
  • TK thymidine kinase gene
  • the HSV TK cassette was obtained from the plasmid pGEM7 (TK), which contains the structural sequences for the HSV TK gene bracketed by the mouse pgk promoter and polyadenylation sequences as described above for pGEM7 (KJ1).
  • telomere sequences from 5' of JK and 3' of C ⁇ was inserted into pGP1b-TK to generate the targeting vector J/C KI (Fig. 20d).
  • the putative structure of the genomic kappa locus following homologous recombination with J/C Kl is shown in Fig. 20e.
  • ES cells used were the AB-1 line grown on mitotically inactive SNL76/7 cell feeder layers (McMahon and Bradley, Cell 62:1073-1085 (1990)) essentially as described (Robertson, E.J. (1987) in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach. E.J. Robertson, ed. (Oxford: IRL Press), p. 71-112).
  • Other suitable ES lines include, but are not limited to, the E14 line (Hooper et al. (1987) Nature 326: 292-295), the D3 line (Doetschman et al. (1985) J. Embrvol. Exp. Morph. 87: 27-45), and the CCE line (Robertson et al.
  • the pluripotence of any given ES cell line can vary with time in culture and the care with which it has been handled.
  • the only definitive assay for pluripotence is to determine whether the specific population of ES cells to be used for targeting can give rise to chimeras capable of germline transmission of the ES genome. For this reason, prior to gene targeting, a portion of the parental population of AB-1 cells is injected into C57B1/6J blastocysts to
  • the kappa chain inactivation vector J/C Kl was digested with NotI and electroporated into AB-1 cells by the methods described (Hasty et al., Nature. 350:243-246 (1991)). Electroporated cells were plated onto 100 mm dishes at a density of 1-2 x 10 6 cells/dish. After 24 hours, G418
  • DNA analysis was carried out by Southern blot hybridization. DNA was isolated from the clones as described (Laird et al., Nucl. Acids Res. 19:4293 (1991)) digested with Xbal and probed with the 800 bp EcoRI/Xbal fragment indicated in Fig. 20e as probe A. This probe detects a 3.7 kb Xbal fragment in the wild type locus, and a diagnostic 1.8 kb band in a locus which has homologously recombined with the
  • the AB1 ES cells are an XY cell line and a majority of these high percentage chimeras were male due to sex conversion of female embryos colonized by male ES cells.
  • Male chimeras derived from 4 of the 5 targeted clones were bred with C57BL/6J females and the offspring monitored for the presence of the dominant agouti coat color indicative of germline transmission of the ES genome.
  • mice homozygous for the mutation approximately 50 percent of the agouti offspring showed a hybridizing Bgl II band of 2.4 kb in addition to the wild-type band of 4.1 kb, demonstrating the germline transmission of the targeted kappa locus.
  • heterozygotes were bred together and the kappa genotype of the offspring determined as described above.
  • three genotypes were derived from the heterozygote matings: wild-type mice bearing two copies of a normal kappa locus, heterozygotes carrying one targeted copy of the kappa gene and one NT kappa gene, and mice homozygous for the kappa mutation. The deletion of kappa sequences from these latter mice was verified by hybridization of the Southern blots with a probe specific for J ⁇ (probe C, Fig. 20a).
  • This example describes the inactivation of the endogenous murine immunoglobulin heavy chain locus by
  • homologous recombination in embryonic stem (ES) cells The strategy is to delete the endogenous heavy chain J segments by homologous recombination with a vector containing heavy chain sequences from which the J H region has been deleted and replaced by the gene for the selectable marker neo.
  • Fig. 21a were isolated from a genomic phage library derived from the D3 ES cell line (Gossler et al., Proc. Natl. Acad. Sci. U.S.A. 83:9065-9069 (1986)) using a J H 4 specific
  • restriction fragment encompassing the mutation with the corresponding sequence from a wild-type neo clone.
  • Hindlll site in the prepared pGEM7 (KJ1) was converted to a Sall site by addition of a synthetic adaptor, and the neo expression cassette excised by digestion with Xbal/Sall. The ends of the neo fragment were then blunted by treatment with the Klenow form of DNA poll, and the neo fragment was
  • pGP1b was digested with the restriction enzyme NotI and ligated with the following oligonucleotide as an adaptor:
  • pGMT mouse immunoglobulin heavy chain targeting
  • HSV Herpes Simplex Virus
  • TK thymidine kinase
  • HSV TK gene was obtained from the plasmid pGEM7 (TK) by digestion with EcoRI and Hindlll. The TK DNA fragment was subcloned between the EcoRI and Hindlll sites of pGMT, creating the plasmid pGMT-TK (Fig. 21c).
  • genomic Xbal/Xhol fragment situated 5' of the J H region, was derived from a positive genomic phage clone by limit digestion of the DNA with Xhol, and partial digestion with Xbal.
  • this Xbal site is not present in genomic DNA, but is rather derived from phage sequences immediately flanking the cloned genomic heavy chain insert in the positive phage clone. The fragment was
  • the final step in the construction involved the excision from pUC18 J H -neo of the 2.8 kb EcoRI fragment which contained the neo gene and flanking genomic sequences 3' of J H . This fragment was blunted by Klenow polymerase and subcloned into the similarly blunted Xhol site of
  • J H KO1 contains 6.9 kb of genomic sequences flanking the J H locus, with a 2.3 kb deletion spanning the J H region into which has been inserted the neo gene.
  • Fig. 21f shows the structure of an endogenous heavy chain gene after homologous recombination with the targeting construct.
  • the heavy chain inactivation vector J H KO1 was digested with NotI and electroporated into AB-1 cells by the methods described (Hasty et al., Nature 350:243-246 (1991)). Electroporated cells were plated into 100 mm dishes at a density of 1-2 x 10 6 cells/dish. After 24 hours, G418
  • DNA analysis was carried out by Southern blot hybridization. DNA was isolated from the clones as described (Laird et al. (1991) Nucleic Acids Res. 19: 4293), digested with StuI and probed with the 500 bp EcoRI/StuI fragment designated as probe A in Fig. 2If. This probe detects a StuI fragment of 4.7 kb in the wild-type locus, whereas a 3 kb band is diagnostic of homologous recombination of endogenous sequences with the targeting vector (see Fig. 21a and f).
  • mice carrying the J H deletion were generated using a neo-specific probe (probe B, Fig. 21f) to generate mice carrying the J H deletion.
  • agouti offspring Since only one copy of the heavy chain locus was targeted in the injected ES clones, each agouti pup had a 50 percent chance of inheriting the mutated locus. Screening for the targeted gene was carried out by Southern blot analysis of stul-digested DNA from tail
  • heterozygotes were bred together and the heavy chain genotype of the offspring determined as described above.
  • three genotypes were derived from the heterozygote atings: wild-type mice bearing two copies of the normal J H locus, heterozygotes caring one targeted copy of the gene and one normal copy, and mice homozygous for the J H mutation.
  • the absence of J H sequences from these latter mice was verified by hybridization of the Southern blots of Stul-digested DNA with a probe specific for J H (probe C, Fig. 21a).
  • the plasmid pBR322 was digested with EcoRI and Styl and ligated with the following oligonucleotides: oligo-42 5'- caa gag ccc gcc taa tga gcg ggc ttt ttt ttg cat act gcg gcc get -3'
  • pGP1a The resulting plasmid, pGP1a, is designed for cloning very large DNA constructs that can be excised by the rare cutting restriction enzyme NotI. It contains a NotI restriction site downstream (relative to the ampicillin resistance gene, AmpR) of a strong transcription termination signal derived from the trpA gene (Christie et al., Proc.
  • This termination signal reduces the potential toxicity of coding sequences inserted into the NotI site by eliminating readthrough transcription from the AmpR gene.
  • this plasmid is low copy relative to the pUC plasmids because it retains the pBR322 copy number control region. The low copy number further reduces the potential toxicity of insert sequences and reduces the selection against large inserts due to DNA replication.
  • the vectors pGP1b, pGP1c, pGP1d, and pGP1f are derived from pGP1a and contain different polylinker cloning sites. The polylinker sequences are given below pGP1a
  • pGP1a was digested with NotI and ligated with the following oligonucleotides: oligo-47 5'- ggc cgc aag ctt act get gga tec tta att aat cga tag tga tct cga ggc -3'
  • oligo-48 5'- ggc cgc etc gag ate act ate gat taa tta agg ate cag cag taa get tgc -3'
  • the resulting plasmid, pGP1b contains a short polylinker region flanked by NotI sites. This facilitates the construction of large inserts that can be excised by NotI digestion.
  • oligonucleotides oligo-44 5'- etc cag gat cca gat ate agt ace tga aac agg get tgc -3'
  • oligo-45 5'- etc gag cat gca cag gac ctg gag cac aca cag cct tec -3' were used to amplify the immunoglobulin heavy chain 3'
  • pNN03 is a pUC derived plasmid that contains a polylinker with the following restriction sites, listed in order: NotI, BamHI, Ncol, Clal, EcoRV, Xbal, Sad, Xhol, SphI, PstI, Bglll, EcoRI, Smal, Kpnl, Hindlll, and NotI).
  • the resulting plasmid, pRE3 was digested with BamHI and Hindlll, and the insert containing the rat Ig heavy chain 3' enhancer cloned into BamHI/Hindlll digested pGP1b.
  • the resulting plasmid, pGPe (Fig. 22 and Table 1), contains several unique restriction sites into which sequences can be cloned and subsequently excised together with the 3' enhancer by NotI digestion.
  • a human placental genomic DNA library cloned into the phage vector XEMBL3/SP6/T7 was screened with the human heavy chain J region specific oligonucleotide: oligo-1 5'- gga ctg tgt ccc tgt gtg atg ctt ttg atg tct ggg gcc aag -3' and the phage clone ⁇ 1.3 isolated.
  • a 4 kb Xhol fragment was isolated from phage clone ⁇ 2.1 that contains sequences immediately downstream of the sequences in pJMl, including the so called ⁇ element involved in (S-associated deleteon of the ⁇ in certain IgD expressing B-cells (Yasui et al., Eur. J. Immunol. 19:1399 (1989), which is incorporated herein by reference).
  • This fragment was treated with the Klenow fragment of DNA polymerase I and ligated to Xhol cut, Klenow treated, pJMl.
  • the resulting plasmid, pJM2 (Fig. 23), had lost the internal Xhol site but retained the 3' Xhol site due to incomplete reaction by the Klenow enzyme.
  • pJM2 contains the entire human J region, the heavy chain J- ⁇ intronic enhancer, the ⁇ switch region and all of the ⁇ constant region exons, as well as the two 0.4 kb direct repeats, ⁇ and ⁇ , involved in ⁇ -associated deletion of the ⁇ gene. 3. Isolation of D region clones and construction of pDH1
  • oligonucleotide oligo-4 5'- tgg tat tac tat ggt teg ggg agt tat tat aac cac agt gtc -3' was used to screen the human placenta genomic library for D region clones. Phage clones ⁇ 4.1 and ⁇ 4.3 were isolated. A 5.5 kb Xhol fragment, that includes the D elements D ⁇ 1 , D N1 , and D M2 (Ichihara et al., EMBO J. 1:4141 (1988)), was isolated from phage clone ⁇ 4.1.
  • pDH1 contains a 10.6 kb insert that includes at least 7 D segments and can be excised with Xhol (5') and EcoRV (3'). 4. pCOR1
  • the plasmid pJM2 was digested with Asp718 (an isoschizomer of Kpnl) and the overhang filled in with the Klenow fragment of DNA polymerase I. The resulting DNA was then digested with Clal and the insert isolated. This insert was ligated to the XhoI/EcoRV insert of pDH1 and Xhol/Clal digested pGPe to generate pCORl (Fig. 24).
  • pIGM1 contains 2 functional human variable region segments, at least 8 human D segments all 6 human J H segments, the human
  • J- ⁇ enhancer the human ⁇ element, the human ⁇ switch region, all of the human ⁇ coding exons, and the human ⁇ element, together with the rat heavy chain 3' enhancer, such that all of these sequence elements can be isolated on a single
  • oligonucleotide specific for human Ig g constant region genes: oligo-29 5'- cag cag gtg cac ace caa tgc cca tga gcc cag aca ctg gac -3' was used to screen the human genomic library. Phage clones 129.4 and ⁇ 29.5 were isolated. A 4 kb Hindlll fragment of phage clone ⁇ 29.4, containing a ⁇ switch region, was used to probe a human placenta genomic DNA library cloned into the phage vector lambda FIXTM II (Stratagene, La Jolla, CA). Phage clone ⁇ Sg1.13 was isolated.
  • a 7.8 kb Hindlll fragment of phage clone ⁇ 29.5, containing the ⁇ 1 coding region was cloned into pUC18.
  • the resulting plasmid, pLT1 was digested with Xhol, Klenow treated, and religated to destroy the internal Xhol site.
  • the resulting clone, pLTlxk was digested with Hindlll and the insert isolated and cloned into pSP ⁇ 2 to generate the plasmid clone pLTlxks.
  • p ⁇ e1 contains all of the 71 constant region coding exons, together with 5 kb of downstream sequences, linked to the rat heavy chain 3' enhancer.
  • a 5.3 kb Hindlll fragment containing the 71 switch region and the first exon of the pre-switch sterile transcript (P. Sideras et al. (1989) International Immunol. 1, 631) was isolated from phage clone XS ⁇ 1.13 and cloned into pSP72 with the polylinker Xhol site adjacent to the 5' end of the insert, to generate the plasmid clone pS ⁇ 1S.
  • the Xhol/Sall insert of pS ⁇ 1S was cloned into Xhol digested p ⁇ e1 to generate the plasmid clone p ⁇ e2 (Fig. 26).
  • p ⁇ e2 contains all of the 71 constant region coding exons, and the upstream switch region and sterile transcript exons, together with 5 kb of downstream sequences, linked to the rat heavy chain 3' enhancer.
  • This clone contains a unique Xhol site at the 5' end of the insert. The entire insert, together with the Xhol site and the 3' rat enhancer can be excised from vector sequences by digestion with NotI. 4 . pHC1
  • pHC1 contains 2
  • Phage clone X49.8 was isolated and a 6.1 kb Xbal fragment containing the variable segment VH49.8 subcloned into pNN03 (such that the polylinker Clal site is downstream of VH49.8 and the polylinker Xhol site is upstream) to generate the plasmid pVH49.8.
  • An 800 bp region of this insert was sequenced, and VH49.8 found to have an open reading frame and intact splicing and recombination signals, thus indicating that the gene is functional (Table 2). 2.
  • a 4 kb Xbal genomic fragment containing the human V H IV family gene V H 4-21 (Sanz et al., EMBO J., 8:3741 (1989)), subcloned into the plasmid pUC12, was excised with Smal and Hindlll, and treated with the Klenow fragment of polymerase I. The blunt ended fragment was then cloned into Clal digested, Klenow treated, pVH49.8. The resulting plasmid, pV2, contains the human heavy chain gene VH49.8 linked upstream of VH4-21 in the same orientation, with a unique Sall site at the 3' end of the insert and a unique Xhol site at the 5' end.
  • sequences immediately upstream of, and adjacent to, the 5.3 kb ⁇ 1 switch region containing fragment in the plasmid p ⁇ e2) together with the neighboring upstream 3.1 kb Xbal fragment were isolated from the phage clone ⁇ Sg1.13 and cloned into Hindlll/Xbal digested pUC18 vector.
  • the resulting plasmid, pS ⁇ 1-5' contains a 3.8 kb insert representing sequences upstream of the initiation site of the sterile transcript found in B-cells prior to switching to the ⁇ 1 isotype (P.
  • transgene constructs to promote correct expression of the sterile transcript and the associated switch
  • the pS ⁇ 1-5' insert was excised with Smal and
  • the ligation product was digested with Sall and ligated to Sall digested pV2.
  • the resulting plasmid, pVP contains 3.8 kb of ⁇ 1 switch 5' flanking sequences linked downstream of the two human variable gene segments VH49.8 and VH4-21 (see Table 2).
  • the pVP insert is isolated by partial digestion with Sall and complete digestion with Xhol, followed by purification of the 15 kb fragment on an agarose gel. The insert is then cloned into the Xhol site of p ⁇ e2 to generate the plasmid clone pVGE1 (Fig. 27).
  • pVGEl contains two human heavy chain variable gene segments upstream of the human ⁇ 1 constant gene and associated switch region.
  • a unique Sall site between the variable and constant regions can be used to clone in D, J, and ⁇ gene segments.
  • the rat heavy chain 3' enhancer is linked to the 3' end of the ⁇ 1 gene and the entire insert is flanked by NotI sites. 5.
  • the plasmid clone pVGEl is digested with Sall and the Xhol insert of pIGMl is cloned into it.
  • the resulting clone, pHC2 contains 4 functional human variable region segments, at least 8 human D segments all 6 human J H segments, the human J-m enhancer, the human ⁇ element, the human ⁇ switch region, all of the human ⁇ coding exons, the human ⁇ element, and the human ⁇ 1 constant region, including the associated switch region and sterile transcript associated exons, together with 4 kb flanking sequences upstream of the sterile transcript initiation site.
  • These human sequences are linked to the rat heavy chain 3' enhancer, such that all of the sequence elements can be isolated on a single fragment, away from vector sequences, by digestion with NotI and
  • transgenic mice A unique Xhol site at the 5' end of the insert can be used to clone in additional human variable gene segments to further expand the recombinational diversity of this heavy chain minilocus.
  • E. Transgenic mice A unique Xhol site at the 5' end of the insert can be used to clone in additional human variable gene segments to further expand the recombinational diversity of this heavy chain minilocus.
  • the NotI inserts of plasmids pIGM1 and pHC1 were isolated from vector sequences by agarose gel electrophoresis. The purified inserts were microinjected into the pronuclei of fertilized (C57BL/6 x CBA) F2 mouse embryos and transferred the surviving embryos into pseudopregnant females as described by Hogan et al. (B. Hogan, F. Costantini, and E. Lacy, Methods of Manipulating the Mouse Embryo, 1986, Cold Spring Harbor
  • mice that developed from injected embryos were analyzed for the presence of transgene sequences by Southern blot analysis of tail DNA. Transgene copy number was estimated by band intensity relative to control standards containing known quantities of cloned DNA. At 3 to 8 weeks of age, serum was isolated from these animals and assayed for the presence of transgene encoded human IgM and IgG1 by ELISA as described by Harlow and Lane (E. Harlow and D. Lane.
  • mice were coated with mouse monoclonal antibodies specific for human IgM (clone AF6, #0285, AMAC, Inc. Westbrook, ME) and human IgG1 (clone JL512, #0280, AMAC, Inc. Westbrook, ME). Serum samples were serially diluted into the wells and the presence of specific immunoglobulins detected with affinity isolated alkaline phosphatase conjugated goat anti-human Ig (polyvalent) that had been pre-adsorbed to minimize cross-reactivity with mouse immunoglobulins. Table 3 and Fig.
  • mice 28 show the results of an ELISA assay for the presence of human IgM and IgG1 in the serum of two animals that developed from embryos injected with the transgene insert of plasmid pHC1. All of the control non- transgenic mice tested negative for expression of human IgM and IgG1 by this assay.
  • Mice from two lines containing the pIGM1 NotI insert (lines #6 and 15) express human IgM but not human IgG1.
  • mice from 6 lines that contain the pHC1 insert and found that 4 of the lines (lines #26, 38, 57 and 122) express both human IgM and human IgG1, while mice from two of the lines (lines #19 and 21) do not express detectable levels of human immunoglobulins.
  • the pHC1 transgenic mice that did not express human immunoglobulins were so-called G o mice that developed directly from microinjected embryos and may have been mosaic for the presence of the transgene.
  • Table 3 shows a correlation between the presence of integrated transgene DNA and the presence of transgene encoded immunoglobulins in the serum. Two of the animals that were found to contain the pHC1 transgene did not express detectable levels of human immunoglobulins. These were both low copy animals and may not have contained complete copies of the transgenes, or the animals may have been genetic mosaics
  • the transgene containing cells may not have populated the hematopoietic lineage.
  • the transgenes may have integrated into genomic locations that are not conducive to their expression.
  • the detection of human IgM in the serum of pIGMl transgenics, and human IgM and IgG1 in pHC1 transgenics, indicates that the transgene sequences function correctly in directing VDJ joining, transcription, and isotype switching.
  • immunoglobulin cDNA clones derived from transgenic mouse spleen mRNA were examined.
  • the overall diversity of the transgene encoded heavy chains, focusing on D and J segment usage, N region addition, CDR3 length distribution, and the frequency of joints resulting in functional mRNA molecules was examined.
  • Transcripts encoding IgM and IgG incorporating VH105 and VH251 were examined.
  • Polyadenylated RNA was isolated from an eleven week old male second generation line-57 pHC1 transgenic mouse.
  • This RNA was used to synthesize oligo-dT primed single
  • cDNA was then used as template for four individual PCR amplifications using the following four synthetic oligonucleotides as primers: VH251 specific oligo-149, eta get cga gtc caa gga gtc tgt gcc gag gtg cag ctg (g,a,t,c); VH105 specific o-150, gtt get cga gtg aaa ggt gtc cag tgt gag gtg cag ctg (g,a,t,c); human gamma1 specific oligo-151, ggc get cga gtt cca cga cac cgt cac egg ttc; and human mu specific oligo-152, cct get cga ggc age caa egg cca cgc tgc teg.
  • Reaction 1 used primers 0-149 and o-151 to amplify VH251-gammal transcripts
  • reaction 2 used o-149 and o- 152 to amplify VH251-mu transcripts
  • reaction 3 used o-150 and o-151 to amplify VH105-gammal transcripts
  • reaction 4 used o-150 and o-152 to amplify VH105-mu transcripts.
  • resulting 0.5 kb PCR products were isolated from an agarose gel; the ⁇ transcript products were more abundant than the ⁇ transcript products, consistent with the corresponding ELISA data (Fig. 34).
  • the PCR products were digested with Xhol and cloned into the plasmid pNN03. Double-stranded plasmid DNA was isolated from minipreps of nine clones from each of the four PCR amplifications and dideoxy sequencing reactions were performed. Two of the clones turned out to be deletions containing no D or J segments. These could not have been derived from normal RNA splicing products and are likely to have originated from deletions introduced during PCR
  • VH105 primer turned out not to be specific for VH105 in the reactions performed. Therefore many of the clones from reactions 3 and 4 contained VH251 transcripts.
  • Table 5 compared the distribution of J segments incorporated into pHC1 transgene encoded transcripts to J segments found in adult human PBL immunoglobulin transcripts. The distribution profiles are very similar, J4 is the dominant segment in both systems, followed by J6. J2 is the least common segment in human PBL and the transgenic animal.
  • Table 7 shows the predicted amino acid sequences of the VDJ regions from 30 clones that were analyzed from the pHC1 transgenic.
  • the translated sequences indicate that 23 of the 30 VDJ joints (77%) are in-frame with respect to the variable and J segments.
  • Table 8 compared the length of the CDR3 peptides from transcripts with in-frame VDJ joints in the pHC1
  • transgenic mouse to those in human PBL.
  • human PBL data comes from Yamada et al.
  • the profiles are similar with the transgenic profile skewed slightly toward smaller CDR3 peptides than observed from human PBL.
  • the average length of CDR3 in the transgenic mouse is 10.3 amino acids. This is substantially the same as the average size reported for authentic human CDR3 peptides by Sanz (J. Immunol. 147:1720- 1729 (1991)).
  • Two human leukocyte genomic DNA libraries cloned into the phage vector XEMBL3/SP6/T7 are screened with a 1 kb Pacl/Hindlll fragment of ⁇ 1.3 containing the human heavy chain J- ⁇ intronic enhancer.
  • Fragments containing functional VJ segments are subcloned into the plasmid vector pSP72 such that the plasmid derived Xhol site is adjacent to the 5' end of the insert seguence.
  • a subclone containing a functional VDJ segment is digested with Xhol and Pad (Pad, a rare-cutting enzyme, recognizes a site near the J-m intronic enhancer), and the insert cloned into Xhol/Pad digested pHC2 to generate a transgene construct with a
  • VDJ segment functional VDJ segment, the J- ⁇ intronic enhancer, the ⁇ switch element, the ⁇ constant region coding exons, and the ⁇ 1 constant region, including the sterile transcript associated sequences, the ⁇ 1 switch, and the coding exons.
  • transgene construct is excised with NotI and microinjected into the pronuclei of mouse embryos to generate transgenic animals as described above.
  • Plasmid vector pGP1a is digested with NotI and the following oligonucleotides ligated in: oligo-81 5'-ggc cgc ate ccg ggt etc gag gtc gac aag ctt teg agg ate cgc-3' oligo-82 5'-ggc cgc gga tec teg aaa get tgt cga cct cga gac ccg gga tgc-3'
  • the resulting plasmid, pGP1c contains a polylinker with Xmal, Xhol, Sall, Hindlll, and BamHI restriction sites flanked by NotI sites.
  • Plasmid vector pGP1a is digested with NotI and the following oligonucleotides ligated in: oligo-87 5'-ggc cgc tgt cga caa get tat cga tgg ate etc gag tgc -3' oligo-88 5'-ggc cgc act cga gga tec ate gat aag ctt gtc gac age -3'
  • the resulting plasmid, pGP1d contains a polylinker with Sall, Hindlll, Clal, BamHI, and Xhol restriction sites flanked by NotI sites.
  • a human placental genomic DNA library cloned into the phage vector ⁇ EMBL3/SP6/T7 (Clonetech Laboratories, Inc., Palo Alto, CA) was screened with the human kappa light chain J region specific oligonucleotide: oligo-36 5'- cac ctt egg cca agg gac aeg act gga gat taa acg taa gca -3' and the phage clones 136.2 and 136.5 isolated.
  • a 7.4 kb Xhol fragment that includes the J ⁇ 1 segment was isolated from
  • pCK1 a C ⁇ vector for expressing rearranged variable segments
  • the resulting clone, pCK1 can accept cloned fragments containing rearranged VJ ⁇ segments into the unique 5' Xhol site.
  • the transgene can then be excised with NotI and purified from vector sequences by gel electrophoresis.
  • the resulting transgene construct will contain the human J-C ⁇ intronic enhancer and may contain the human 3' ⁇ enhancer. 2.
  • pCK2 a C ⁇ vector with heavy chain enhancers for
  • pMHEl human heavy chain J- ⁇ intronic enhancer
  • pMHE2 BamHI/Hindlll fragment. This 2.3 kb fragment is isolated and cloned into pGP1c to generate pMHE2.
  • pMHE2 is digested with Sall and the 13 kb Xhol insert of p36.5 cloned in.
  • the resulting plasmid, pCK2 is identical to pCK1, except that the mouse and human heavy chain J- ⁇ intronic enhancers are fused to the 3' end of the transgene insert.
  • analogous constructs can be generated with different enhancers, i.e. the mouse or rat 3' kappa or heavy chain enhancer (Meyer and Neuberger, EMBO J..
  • V ⁇ specific oligonucleotide oligo-65 5'-agg ttc agt ggc agt ggg tct ggg aca gac ttc act etc ace ate age-3'
  • VJ ⁇ segment Clones that hybridized with both V and J probes are isolated and the DNA sequence of the rearranged VJ ⁇ segment determined.
  • Fragments containing functional VJ segments are subcloned into the unique Xhol sites of vectors pCK1 and pCK2 to generate
  • transgene constructs are isolated from vector sequences by digestion with NotI. Agarose gel purified insert is microinjected into mouse embryo pronuclei to generate transgenic animals.
  • Animals expressing human kappa chain are bred with heavy chain minilocus containing transgenic animals to generate mice expressing fully human antibodies.
  • VJK combinations may be capable of forming stable heavy-light chain complexes with a broad spectrum of different heavy chain VDJ combinations
  • several different light chain transgene constructs are generated, each using a different rearranged VJk clone, and transgenic mice that result from these constructs are bred with heavy chain minilocus transgene expressing mice.
  • Peripheral blood, spleen, and lymph node lymphocytes are isolated from double transgenic (both heavy and light chain constructs) animals, stained with fluorescent antibodies specific for human and mouse heavy and light chain immunoglobulins (Pharmingen, San Diego, CA) and analyzed by flow cytometry using a FACScan analyzer (Becton Dickinson, San Jose, CA).
  • Rearranged light chain transgenes constructs that result in the highest level of human heavy/light chain complexes on the surface of the highest number of B cells, and do not adversely affect the immune cell compartment (as assayed by flow cytometric
  • the 13 kb CK containing Xhol insert of p36.5 is treated with Klenow enzyme and cloned into Hindlll digested, Klenow-treated, plasmid pGPld.
  • a plasmid clone is selected such that the 5' end of the insert is adjacent to the vector derived Clal site.
  • the resulting plasmid, p36.5-ld is digested with Clal and Klenow-treated.
  • the J ⁇ l containing 7.4 kb Xhol insert of p36.2 is then Klenow-treated and cloned into the Clal, Klenow-treated p36.5-ld.
  • a clone is selected in which the p36.2 insert is in the same orientation as the p36.5 insert.
  • This clone, pJCKl (Fig. 34), contains the entire human JK region and C ⁇ , together with 7.2 kb of upstream sequences and 9 kb of downstream sequences.
  • the insert also contains the human J-C ⁇ intronic enhancer and may contain a human 3' ⁇ enhancer.
  • the insert is flanked by a unique 3' Sall site for the purpose of cloning additional 3' flanking sequences such as heavy chain or light chain enhancers.
  • a unique Xhol site is located at the 5' end of the insert for the purpose of cloning in unrearranged VK gene segments.
  • the unique Sall and Xhol sites are in turn flanked by NotI sites that are used to isolate the completed transgene construct away from vector sequences. 2. Isolation of unrearranged V ⁇ gene segments and generation of transgenic animals expressing human Ig light chain protein
  • V ⁇ specific oligonucleotide cligo-65 (discussed above), is used to probe a human placental genomic DNA library cloned into the phage vector 1EMBL3/3P6/T7 (Clonetech).
  • DNA fragments containing selected variable gene segments are cloned into the unique Xhol site of plasmid pJCK1 to generate minilocus constructs.
  • the resulting clones are digested with NotI and the inserts isolated and injected into mouse embryo pronuclei to generate transgenic animals.
  • the transgenes of these animals will undergo V to J joining in developing B-cells.
  • Animals expressing human kappa chain are bred with heavy chain minilocus containing transgenic animals to generate mice expressing fully human antibodies.
  • This Example describes the cloning of a human genomic heavy chain immunoglobulin transgene which is then introduced into the murine germline via microinjection into zygotes or integration in ES cells.
  • Nuclei are isolated from fresh human placental tissue as described by Marzluff, W.F., et al. (1985),
  • the isolated nuclei (or PBS washed human spermatocytes) are embedded in 0.5% low melting point agarose blocks and lyse with 1 mg/ml proteinase K in 500mM EDTA, 1% SDS for nuclei, or with lmg/ml proteinase K in 500mM EDTA, 1% SDS, lOmM DTT for spermatocytes at 50°C for 18 hours.
  • the proteinase K is inactivated by incubating the blocks in 40 ⁇ g/ml PMSF in TE for 30 minutes at 50°C, and then washing extensively with TE.
  • the DNA is then digested in the agarose with the restriction enzyme NotI as described by M. Finney in Current Protocols in Molecular Biology (F. Ausubel et al., eds. John Wiley & Sons, Supp. 4, 1988, e.g., Section 2.5.1).
  • the NotI digested DNA is then fractionated by pulsed field gel electrophoresis as described by Anand et al., Nuc. Acids Res. 17:3425-3433 (1989). Fractions enriched for the NotI fragment are assayed by Southern hybridization to detect one or more of the sequences encoded by this fragment. Such sequences include the heavy chain D segments, J segments, and ⁇ I constant regions together with representatives of all 6 V H families (although this fragment is identified as 670 kb fragment from HeLa cells by Berman et al. (1988), supra., we have found it to be an 830 kb fragment from human placental and sperm DNA). Those fractions containing this NotI
  • Plasmid pYACNN is prepared by digestion of pYACneo (Clontech) with EcoRI and ligation in the presence of the oligonucleotide 5' - AAT TGC GGC CGC - 3'.
  • YAC clones containing the heavy chain NotI fragment are isolated as described by Traver et al., Proc. Natl. Acad. Sci. USA. 86:5898-5902 (1989).
  • the cloned NotI insert is isolated from high molecular weight yeast DNA by pulse field gel electrophoresis as described by M. Finney, op. cit.
  • the DNA is condensed by the addition of 1 mM spermine and
  • the DNA is isolated by pulsed field gel electrophoresis and introduced into ES cells by lipofection (Gnirke et al., EMBO J. 10:1629-1634 (1991)), or the YAC is introduced into ES cells by spheroplast fusion.
  • the two fragments are coinjected into the nucleus of a mouse single cell embryo as described in Example 1.
  • An antigen of interest is used to immunize (see
  • the spleen is removed, and spleen cells used to generate hybridomas. Cells from an individual hybridoma clone that secretes
  • genomic DNA antibodies reactive with the antigen of interest are used to prepare genomic DNA.
  • a sample of the genomic DNA is digested with several different restriction enzymes that recognize unique six base pair sequences, and fractionated on an agarose gel.
  • Southern blot hybridization is used to identify two DNA fragments in the 2-10 kb range, one of which contains the single copy of the rearranged human heavy chain VDJ sequences and one of which contains the single copy of the rearranged human light chain VJ sequence. These two fragments are size fractionated on agarose gel and cloned directly into pUC18. The cloned inserts are then subcloned respectively into heavy and light chain expression cassettes that contain constant region sequences.
  • the plasmid clone p ⁇ el (Example 12) is used as a heavy chain expression cassette and rearranged VDJ sequences are cloned into the Xhol site.
  • the plasmid clone pCK1 is used as a light chain expression cassette and rearranged VJ
  • sequences are cloned into the Xhol site.
  • the resulting clones are used together to transfect SP 0 cells to produce antibodies that react with the antigen of interest (Co. et al., Proc. Natl. Acad. Sci. USA 88:2869 (1991), which is incorporated herein by reference).
  • mRNA is isolated from the cloned hybridoma cells described above, and used to synthesize cDNA.
  • the expressed human heavy and light chain VDJ and VJ sequence are then amplified by PCR and cloned (Larrick et al., Biol. Technology, 7:934-938 (1989)).
  • oligonucleotides are synthesized that encode the same polypeptides, and synthetic expression vectors generated as described by Queen et al., Proc. Natl. Acad. Sci. USA., 84: 5454-5458 (1989).
  • transgenic animals can be successfully immunized with complex antigens such as those on human red blood cells and respond with kinetics that are similar to the response kinetics observed in normal mice.
  • Blood cells generally are suitable immunogens and comprise many different types of antigens on the surface of red and white blood cells.
  • Tubes of human blood from a single donor were collected and used to immunize transgenic mice having
  • J H D functionally disrupted endogenous heavy chain loci
  • HCI human heavy chain minigene construct
  • mice are designated as line 112.
  • Blood was washed and resuspended in 50 mis Hanks' and diluted to 1x10 8 cells/ml 0.2 mis (2x10 7 cells) were then injected interperitoneally using a 28 gauge needle and 1 ce syringe. This immunization protocol was repeated approximately weekly for 6 weeks. Serum titers were monitored by taking blood from retro-orbital bleeds and collecting serum and later testing for specific antibody. A pre-immune bleed was also taken as a control. On the very last immunization, three days before these animals were sacrificed for serum and for hybridomas, a single immunization of 1 x 10 7 cells was given intravenously through the tail to enhance the production of hybridomas.
  • Mice # 2343 and 2348 have a desired phenotype: human heavy chain mini-gene transgenic on heavy chain knock-out
  • Hybridomas were generated by fusing mouse spleen cells of approximately 16 week-old transgenic mice (Table 9) that had been immunized as described (supra) to a fusion partner consisting of the non-secreting HAT-sensitive myeloma cell line, X63 Ag8.653.
  • Hybridoma clones were cultivated and hybridoma supernatants containing immunoglobulins having specific binding affinity for blood cell antigens were
  • Serum and hybridoma supernatants were tested using flow cytometry.
  • Red blood cells from the donor were washed 4X in Hanks' balanced salt solution and 50,000 cells were placed in 1.1 ml polypropylene microtubes.
  • Cells were incubated with antisera or supernatant from the hybridomas for 30 minutes on ice in staining media (lx RPMI 1640 media without phenol red or biotin (Irvine Scientific) 3% newborn calf serum, 0.1% Na azide). Controls consisted of littermate mice with other genotypes. Cells were then washed by centrifugation at 4°C in Sorvall RT600B for 5-10 minutes at 1000 rpm.
  • mice and littermate controls Serum of transgenic mice and littermate controls was incubated with either red blood cells from the donor, or white blood cells from another individual, washed and then developed with anti-human IgM FITC labeled antibody and analyzed in a flow cytometer. Results showed that serum from mice that are transgenic for the human mini-gene locus (mice 2343 and 2348) show human IgM reactivity whereas all littermate animals (2344, 2345, 2346, 2347) do not. Normal mouse serum (NS) and phosphate buffer saline (PBS) were used as negative controls. Red blood cells were ungated and white blood cells were gated to include only lymphocytes. Lines are drawn on the x and y axis to provide a reference. Flow cytometry was performed on 100 supernatants from fusion 2348. Four supernatants showed positive reactivity for blood cell antigens.
  • NS normal mouse serum
  • PBS phosphate buffer saline
  • the vector pGP1b (referred to in a previous example) is digested with Xhol and BamHI and ligated with the following oligonucleotides: 5'- gat cct cga gac cag gta cca gat ctt gtg aat teg -3'
  • This plasmid contains a polylinker that includes the following restriction sites:
  • a 0.8 kb Xbal/Bglll fragment of pVH251 (referred to in a previous example), that includes the promoter leader sequence exon, first intron, and part of the second exon of the human VH-V family immunoglobulin variable gene segment, was inserted into Xbal/Bglll digested vector pNN03 to generate the plasmid pVH251.
  • the BamHI/Hindlll fragment of pMHEl is cloned into BamHI/Hindlll cut pVhgh to generate the B-cell expression vector pBCE1.
  • This vector depicted in Fig. 36, contains unique Xhol and Asp718 cloning sites into which antisense DNA fragments can be cloned.
  • the expression of these antisense sequences is driven by the upstream heavy chain promoter- enhancer combination the downstream hGH gene sequences provide polyadenylation sequences in addition to intron sequences that promote the expression of transgene constructs.
  • Antisense transgene constructs generated from pBCEl can be separated from vector sequences by digestion with NotI.
  • PCR polymerase chain reaction
  • the resulting 0.3 kb PCR product is digested with Asp7l8 and Xhol and cloned into Asp718/XhoI digested pBCE1 to generate the antisense transgene construct pMASl.
  • the purified NotI insert of pMAS1 is microinjected into the pronuclei of half day mouse embryos-- alone or in combination with one or more other transgene constructs--to generate transgenic mice.
  • This construct expresses an RNA transcript in B-cells that hybridizes with mouse IgM mRNA, thus down-regulating the expression of mouse IgM protein.
  • Double transgenic mice containing pMAS1 and a human heavy chain transgene minilocus such as pHC1 will express the human transgene encoded Ig receptor on a higher percentage of B-cell than mice transgenic for the human heavy chain minilocus alone.
  • the ratio of human to mouse Ig receptor expressing cells is due in part to competition between the two populations for factors and cells that promoter B-cell differentiation and expansion. Because the Ig receptor plays a key role in B-cell
  • mouse Ig receptor expressing B-cells that express reduced levels of IgM on their surface (due to mouse Ig specific antisense down-regulation) during B-cell development will not compete as well as cells that express the human receptor.
  • RNA transcript in B-cells that hybridizes with mouse IgK mRNA, thus down-regulating the expression of mouse IgK protein as described above for pMAS1.
  • This example demonstrates the successful immunization and immune response in a transgenic mouse of the present invention.
  • KLH-DNP Keyhole limpet hemocyanin conjugated with greater than 400 dinitrophenyl groups per molecule (Calbiochem, La Jolla, California) (KLH-DNP) was alum precipitated according to a previously published method (Practical Immunology, L. Hudson and F.C. Hay, Blackwell Scientific (Pubs.), p. 9, 1980).
  • PBS phosphate buffered saline

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Abstract

L'invention concerne des animaux transgéniques non humains pouvant produire des anticorps hétérologues ainsi que des animaux transgéniques non humains ayant des gènes d'immunoglobuline inactivée endogènes. Dans un aspect de l'invention, les gènes endogènes d'immunoglobuline sont supprimés par des polynucléotides antisens et/ou par un antisérum dirigé contre des immunoglobulines endogènes. Les anticorps hétérologues sont codés par des gènes d'immunoglobuline que l'on ne trouve pas normalement dans le génome de cette espèce d'animal non humain. Dans un aspect de l'invention, un ou plusieurs transgènes contenant des séquences de chaînes lourdes d'immunoglobulines humaines hétérologues non réagencées sont introduites dans un animal non humain formant ainsi un animal transgénique capable de réagencer fonctionnellement des séquences d'immunoglobuline transgénique et de produire un répertoire d'anticorps d'isotypes divers codés par des gènes d'immunoglobuline humains. De tels anticorps humains hétérologues sont produits dans des cellules B qui sont par la suite immortalisées, par exemple par fusion avec une lignée cellulaire d'immortalisation telle qu'un myélome ou par manipulation de ces cellules B à l'aide d'autres techniques pour perpétuer une lignée cellulaire capable de produire un anticorps hétérologue monoclonal. L'invention concerne également des transgènes d'immunoglobuline à chaîne lourde et légère pour produire de tels animaux transgéniques non humains ainsi que des procédés et des vecteurs d'éclatement des loci d'immunoglobuline endogène chez l'animal transgénique.
PCT/US1992/010983 1990-08-29 1992-12-17 Animaux transgeniques non humains capables de produire des anticorps heterologues Ceased WO1993012227A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
JP5511191A JPH07503132A (ja) 1991-12-17 1992-12-17 異種抗体を産生することができるトランスジェニック非ヒト動物
EP93901143A EP0746609A4 (fr) 1991-12-17 1992-12-17 Animaux transgeniques non humains capables de produire des anticorps heterologues
CA002124967A CA2124967C (fr) 1991-12-17 1992-12-17 Animaux transgeniques non humains capables de produire des anticorps heterologues
US08/053,131 US5661016A (en) 1990-08-29 1993-04-26 Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US08/544,404 US5770429A (en) 1990-08-29 1995-10-10 Transgenic non-human animals capable of producing heterologous antibodies
US11/009,769 US20060026703A1 (en) 1990-08-29 2004-12-10 Transgenic non-human animals for producing heterologous and chimeric antibodies
US11/009,873 US7501552B2 (en) 1991-08-28 2004-12-10 Transgenic non-human animals for producing chimeric antibodies
US11/009,840 US20060015949A1 (en) 1990-08-29 2004-12-10 Transgenic non-human animals for producing heterologous and chimeric antibodies

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US07/810,279 US5569825A (en) 1990-08-29 1991-12-17 Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US07/810,279 1991-12-17
US07/853,408 US5789650A (en) 1990-08-29 1992-03-18 Transgenic non-human animals for producing heterologous antibodies
US07/853,408 1992-03-18
US90406892A 1992-06-23 1992-06-23
US07/904,068 1992-06-23

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WO1993012227A1 true WO1993012227A1 (fr) 1993-06-24

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PCT/US1992/010983 Ceased WO1993012227A1 (fr) 1990-08-29 1992-12-17 Animaux transgeniques non humains capables de produire des anticorps heterologues

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EP (1) EP0746609A4 (fr)
JP (2) JPH07503132A (fr)
AU (1) AU3328493A (fr)
CA (1) CA2124967C (fr)
WO (1) WO1993012227A1 (fr)

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JPH07503132A (ja) 1995-04-06
CA2124967A1 (fr) 1993-06-24
JP2004008218A (ja) 2004-01-15
AU3328493A (en) 1993-07-19
EP0746609A1 (fr) 1996-12-11
CA2124967C (fr) 2008-04-08

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