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WO1990008779A1 - Anticorps anti-idiotypes reagissant avec des idiotopes partages exprimes par des lymphomes humains et des auto-anticorps - Google Patents

Anticorps anti-idiotypes reagissant avec des idiotopes partages exprimes par des lymphomes humains et des auto-anticorps Download PDF

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WO1990008779A1
WO1990008779A1 PCT/US1990/000424 US9000424W WO9008779A1 WO 1990008779 A1 WO1990008779 A1 WO 1990008779A1 US 9000424 W US9000424 W US 9000424W WO 9008779 A1 WO9008779 A1 WO 9008779A1
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antibody
pair
monoclonal antibodies
human monoclonal
antisera
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Richard Alan Miller
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Idec Pharmaceuticals Corp
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Idec Pharmaceuticals Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
    • C07K16/4258—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig
    • C07K16/4266—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig against anti-tumor receptor Ig
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention is in the field of immunodiag- nosis and immunotherapy. Specifically, the invention relates to the discovery of antibodies that may be used in the prevention, diagnosis, monitoring, treatment, and amelioration of autoimmune diseases, HIV associated B-cell lymphomas, and B-cell lymphomas generally.
  • Antibodies are produced by the B-cells (B-lymphocytes) of the immune system of animals for the purpose of recognizing and contributing to the elimination of foreign substances found within the host mammal. Any foreign substance, typically but not exclus ⁇ ively a protein, that induces such an antibody response by the host, is termed an antigen. Upon antigen stimulation, mature B-cells differentiate into plasma cells that pro ⁇ liferate and secrete antigen specific antibodies into the serum.
  • Immunoglobulins are Y-shaped, tetrameric molecules consisting of two relatively bong polypeptide chains called heavy (H) chains and two shorter polypeptide chains called light (L) chains. Each pair of arms of the Y- shaped structure has specific antigen binding properties and each arm is referred to as an antigen-binding fragment (Fab region) .
  • the tail (or base) of the Y structure is a crystallizable fragment (Fc) that includes the binding site for activating cytolytic activity (the Fc region) .
  • Immunoglobulin molecules possess variable regions that are responsible for their specific antigen recogni- tion.
  • the features that distinguish one immunoglobulin variable region from another are collectively termed the antibody "idiotype,” which is derived from the Greek for "private form.”
  • the variable region idiotypes contain and are defined by a plurality of determinants, termed "idio ⁇ topes.”
  • idio ⁇ topes consist of three dimensional configurations of various peptides that make up the poly ⁇ peptide chains of the Fab regions; like foreign protein antigens, each idiotope is immunogenic and capable of eliciting anti-idiotype immune responses (antibodies spe ⁇ cific for an individual idiotope or group of idiotopes) .
  • variable region is encoded for by V H , D and J H gene segments for the heavy chain and V L and J L gene segments for the light chain. (See Tonegawa, S., Nature 302:575 (1983).) It is the combination of these genetic elements that creates distinct antigenic determinants, or idiotopes, within the immunoglobulin variable regions. Idiotopes may be shared (e.g.. "public”) or not shared (e.g.. "private”) . These terms and the concept of shared idiotopes are explained below.
  • An antibody whose formation is stimulated by administration of an antigen can bind the antigen through non-covalent bonds. This binding is postulated to be based on topographic complementarity of the antibody binding site with the binding site of the antigen, (applicant does not, however, presume any specific means through which such binding may actually occur.)
  • the binding site of the antigen, which is thereby recognized by the antibody is termed the "epitope" and the binding site on the antibody is termed the "paratope.”
  • a paratope may serve as an idiotope, i.e..
  • the paratope may stimulate an anti-idiotypic response in which, like the original epitope, the anti-idiotypic antibodies bind to the paratope. If an anti-paratope anti-idiotope antibody structurally mimics the antigen it is called the "internal image" of the antigen.
  • an anti-paratope anti-idiotope antibody structurally mimics the antigen it is called the "internal image" of the antigen.
  • other anti-idiotypic antibodies define antibody and T-cell receptor idiotopes that parti ⁇ cipate in the regulation of immune responses. These idiotypes are termed "regulatory idiotypes" and they are not necessarily the internal images of the original anti- gen. (See, e.g.. Burdette, S. and Schwartz, R. , New Eng. J. of Med.
  • V H and V L gene segments Different gene segments can be expressed in different combinations for different anti- genic binding properties. Secondly, V H or V L genes may be combined with different D and J gene segments. Thirdly, different V H and V L chains may be combined in different ways. These factors are the cause of the diversity of immunoglobulin expression observed in mammals. Somatic mutations occur in B-cells that further increase diversity.
  • the body may produce more than one antibody molecule reactive with that epitope.
  • These antibodies may differ in the constant region or the variable region of the light or heavy chain. Within a species, differences may be seen in the heavy chain constant region. These differences are known as "isotypes" and refer to different immunoglobulin classes and subclasses within the immune system, e.g. , IgGl, IgG2, IgG3, IgG4, IgM, igAl, IgA2, and IgE in humans. These structural differences provide different immunoglobulin molecules with specific effector functions such as ability to fix complement, to increase phagocytosis by macro- phages, etc.
  • allo- types additional inherited differences in heavy chain constant region structure may occur and are termed "allo- types."
  • the allotypic regions of the heavy chain constant region are derived from genes that are inherited from each of the individual's parents.
  • the differences in antibody molecule seen in the immunoglobulin variable regions are a result of the use of particular V H and V L genes by the B-cell as it differentiates into an antibody producing plasma cell.
  • an antibody reactive with a particular epitope present on an antigen may use different heavy chain constant regions, different light chain constant regions (either kappa or lambda) , or may select different V L or V H gene segments.
  • variable region gene segments may be constructed that maintain the appropriate complementarity and reactivity with the epitope.
  • Antiidiotypic antibodies react with particular sections (idiotopes) of the immunoglobulin variable regions. Antibodies reactive with defined epitopes are more likely to utilize particular V H or V L gene segments than randomly selected antibodies.
  • the particular antigenic determinant or "epitope" within the variable region that is defined by an anti-idiotype anti ⁇ body is known as an idiotope.
  • idiotope The particular antigenic determinant or "epitope" within the variable region that is defined by an anti-idiotype anti ⁇ body is known as an idiotope.
  • idiotope many idiotopes exist within immunoglobulin variable light and variable heavy chain segments, or are defined by three dimensionally contiguous regions of heavy and light chains. Because of the tremendous diversity generated within the immunoglobulin gene system, cross-reactivity of anti- idiotypes rarely is seen and not expected.
  • lymphomas have shared idiotopes suggests that either these idiotopes are reactive with similar antigenic determinants (for example, antigens associated with pathogenesis) or that the malignant B-cells are pre-disposed to select particu ⁇ lar V H or V L gene segments in the malignant process.
  • Antibodies are only one component of the animal immune response system. Whenever antibodies bind to foreign protein, they effectuate a wide range of events that may eventually lead to the destruction of the recog ⁇ nized antigen.
  • Antibodies are manufactured by B-cells, which are a type of lymphocyte. A B-cell carries a sample of the particular antibody which that cell manufactures on its cell surface. As previously discussed, stimulation of this cell surface antibody by binding of an antigen will stimulate the B-cell to differentiate into a plasma cell that secretes serum antibodies in a positive feedback loop. For example, when an antigen is introduced into the bloodstream, it may come into contact with existing circu- lating serum antibodies. In such a case, the antigen would not reach the particular B-cell and would not cause such stimulation and differentiation. However, if the antigen introduced is in excess of the available circu ⁇ lating antibody, then stimulation of further antibody production can occur through this mechanism.
  • B-cells are antibody producing cells, each expressing a different antibody on its surface.
  • the human body has the potential to express an enormous number of antibodies (i.e.. 10 7 to 10 8 ) .
  • One type of cancer resulting from proliferation of a particular B-cell is a B-cell lymphoma.
  • B-cell lymphoma As a result of he diversity of B-cells, it is unexpected that any two or more B-cell lymphomas would express the same antibody idiotype on their cell surfaces.
  • AIDS is a fatal disease caused by the HIV virus that is often accompanied by opportunistic infections and can- cers, such as B-cell lymphomas.
  • these lymphomas generally are high grade lymphomas and have a poor prog ⁇ nosis due.to their rapidly progressive clinical course, with most patients not surviving more than six months.
  • B-cell lymphomas generally, cell surface antibodies produced by AIDS associated B-cell lymphomas are expected to be diverse in character. Thus, it is unexpected that these antibodies would share antigenic determinants (known as idiotopes) with each other.
  • B-cell lymphoma malignant B-cells, like their normal counterparts, express unique idiotypic determinants on their surface that may be exploited as "tumor- associated antigen" markers for immunotherapy.
  • the activity of anti-idiotypes in B-cell lymphoma therapy has been demon ⁇ strated in several animal models.
  • one of the inherent problems in developing effective anti-idiotype immunotherapy is the presence in the patient serum of circulating idiotypes derived from either tumor or normal B-cells that react with the administered anti ⁇ body. Such circulating antibodies will neutralize administered anti-idiotype antibodies and prevent the administered antibody from reaching the tumor target, thereby blocking its therapeutic effect.
  • Meeker et al. _ Blood 65:1349 (1985) shows that one cannot achieve an anti-tumor response if there is too high a level of circulating idiotype.
  • one of the objects of the present invention is to develop antiidiotypes that do not react with shared idiotopes expressed in high levels in the plasma, since this would limit the use of such an anti-idiotype in therapy.
  • anti-idiotype immunotherapy is limited by the current requirement for customized development of hybridomas producing anti-idiotype antibodies for each individual patient's tumor.
  • the time required to develop an antiidiotype on a custom basis may preclude treatment of some patients with late stage or rapidly progressing forms of disease. Additionally, the cost associated with patient customized anti-idiotype therapy may limit its application. Accordingly, it is an object of the present invention to develop anti-idiotypes recognizing shared idiotopes (shared anti-idiotypes) expressed by a relevant population of lymphomas.
  • shared anti-idiotypes shared anti-idiotypes
  • Stevenson, et al.. attempted to identify anti ⁇ idiotypes for use in therapy against more than one B-cell lymphoma (shared antiidiotypes) . Their work suggests that anti-idiotypes reactive with idiotopes present in normal human serum would be most likely to react with shared idiotopes. By only looking at a limited number of anti ⁇ bodies, however, Stevenson, et al. ended up with only a few anti-idiotypes that reacted with a very small propor ⁇ tion of the lymphomas in the B-cell lymphomas that they were studying.
  • CLL cells are derived from CD-5+ lymphocytes in over 90% of patients. This is different from other lymphomas such as B-cell non-Hodgkin's lymphomas (“NHL”) where presumably any of the very wide variety of B-cells could be transformed to malignancy.
  • Kipps, e al.. results showed that 25% of the V k region of the cell surface antibodies in CLL were the same. Since CLL cells are derived from a particular subset of B-cells, i.e.. those which are CD5+, it is not surprising that they are closely related.
  • CLL For CLL, the high frequency expression of a conserved kappa light chain variable region gene explains the high incidence of a cross-reactive idiotype. As noted by Kipps, et al.. this idiotype is not expressed in high frequency in follicular lymphomas. It is likely that the cells of CLL represent a special example in that they are CD5 positive. CD5 positive cells are known to be associ- ated with autoreactive antibodies that also possess cross- reactive idiotypes (see Blood 72:422 (1988)).
  • Autoimmune diseases such as systemic lupus erythema- tosus (“SLE”) and rheumatoid arthritis (“RA”) are associa- ted with antibodies that react with host self antigens.
  • Such autoreactive antibodies or autoantibodies may react with DNA, immunoglobulin constant region determinants, nuclear proteins, RNA, cardiolipin, thyroglobulin, red cell antigens, platelet antigens, or other self antigens.
  • Antibody 16.6 is a DNA reactive autoantibody that was originally isolated from a patient with SLE.
  • the 16.6 antibody contains an idiotype that is frequently expressed by autoantibodies found in patients with SLE and in some patients with RA. Thus, the 16-6 idiotype is shared among patients with these diseases.
  • Rheumatoid factors are autoantibodies reactive with immunoglobulin constant region determinants. RFs are found associated with many autoimmune diseases but are particularly important in rheumatoid arthritis where levels of the RF autoantibody correlate with disease activity.
  • the prior art teaches that RFs are a polyclonal mixture of many antibodies and, thus, they would not be expected to express a dominant or restricted idiotype. Therefore, it would be unusual to find a shared idiotype expressed by both lymphomas and autoantibodies with disease antigen reactivity.
  • the discovery of anti-idiotype antibodies reactive with shared idiotypes in lymphoma and autoimmune disease would greatly facilitate the use of antibodies in diagnosis and therapy of auto ⁇ immune as well as lymphoma diseases.
  • an anti-idiotype antibody Prior to the present invention, due to the tremendous diversity of the B-cell population, an anti-idiotype antibody had to be prepared on a customized basis for use in diagnosis or treatment of lymphoma or autoimmune disease. This is difficult, time consuming, and expensive. Accordingly, it is an addi- tional object of the present invention to develop preform- ulated anti-idiotype antibodies reactive with shared idiotopes that can be used with greater efficiency in evaluation, diagnosis, and therapy of lymphoma and/or autoimmune diseases.
  • the present invention is based on the discovery of a panel of at least 32 anti- idiotype antibodies that react with shared idiotypes expressed in varying frequencies in different histologic subsets of B-cell lymphomas and autoantibodies associated with autoimmune disease. See Table 2. More specifically, applicant has found that 108 out of 332 B-cell lymphoma cases (32.5%), including 35 of 116 follicular small cleaved lymphomas (30%) , react with at least one out of 32 anti-idiotype antibodies. With respect to AIDS-associated lymphomas, applicant has found that five anti-idiotype antibodies react with 12 of 15 of such lymphoma cases. See Table 3.
  • applicant has identified at least seven anti-B-cell lymphoma antibody that also binds selected autoantibodies. See Table 6. This degree of cross-reactivity is high, and certainly not predictable. Applicant discloses and claims herein these and other novel anti-antibodies that may be useful in the treatment, diagnosis and/or monitoring of autoimmune diseases, AIDS- and non-AIDS-associated lymphomas.
  • Figure 1 shows a competitive inhibition ELISA used as the primary screen for anti-idiotype monoclonal antibodies reactive with shared idiotopes in normal human serum. Compared to horse serum, human serum produced a greater than four-fold inhibition of binding of monoclonal anti- idiotype antibody C3 3-13-8 to shared idiotope on the idiotype derived from the tumor.
  • Figure 2 shows a second-stage quantitation assay of anti-idiotype binding to immunoglobulin in pooled human serum.
  • Serial dilutions of anti-idiotype C33-13-8 with pooled human serum generate a curve that is similar to the competitive inhibition curve produced by incubation of C33-13-8 monoclonal antibody with serial dilutions of purified idiotype at a starting concentration of 25 /xg/ml.
  • Comparison of the midpoints of the curves reveals a con ⁇ centration of immunoglobulin bearing the shared idiotope in serum calculated to be 32 ⁇ g/ml.
  • Figure 3 uses three large circles to schematically represent the idiotype structures for patients Fa, Tr and
  • C33-13-8 and C33-23 define shared idiotopes expressed by tumor cells from these three patients.
  • Other idiotopes are defined by anti-idiotypes that are private because of their lack of cross-reactivity with other patients.
  • Overlapping small circles indicate idiotopes defined by reactivity with two or more anti-idiotype antibodies, said idiotopes being at the same or nearby positions as determined by anti-idiotype competitive binding studies.
  • Figure 4 is a graph showing the results of immuno fluorescence staining and FACS analysis performed using tumor cells from patients Du(IgMK), Me(IgGK), St(IgML), and Ei(IgML).
  • the immunoglobulin bearing cells were iden ⁇ tified by staining with anti-immunoglobulin light chain reagents which illustrate total B-cells v. that proportion of cells in the population that represented the tumor clone. Negative control staining was identical to that seen by staining with the inappropriate light chain reagent.
  • S37-48-6-2-6 (anti-shared idiotope) reacted with cells from patient Du, St and Ei. Tumor cells from patients St and Ei also were stained with private anti ⁇ idiotypes.
  • S37-48-6-2-6 did not react with patient Me cells.
  • Figure 5 depicts the level of the L50-19 shared idio- type over time in a patient A with rheumatoid arthritis and the correlation of idiotype level to disease progressive ⁇ sion and remission.
  • Figure 6 depicts the level of the L50-19 shared idio ⁇ type over time in a patient B with rheumatoid arthritis and the correlation of idiotype level to disease progressive ⁇ sion and remission.
  • Figure 7 depicts the level of the L50- 19 shared idiotype over time in a patient C with rheumatoid arth ⁇ ritis and the correlation of idiotype level to disease progression and remission.
  • Applicant has produced at least 199 monoclonal anti-idiotypes directed against the tumors of 67 patients with low grade, follicular, B-cell lymphomas.
  • Low grade follicular B-cell lymphoma is one of the more common types of B-cell lymphomas.
  • the diagnosis is based on clinical features and histologic appearance.
  • applicant screened this panel of anti-idiotypes using a modification of the technique described by Stevenson, et al.. Blood 68:430 (1986). Using this technique, anti ⁇ idiotypes reactive with minor components of normal serum immunoglobulin were selected and examined for their cross-reactivity against a collection of lymphomas and other proteins, e .g., autoantibodies.
  • Applicant also has found that some anti-idiotypes produced against non-HIV associated B-cell lymphomas react with shared idiotopes expressed on non-HIV associated and HIV associated B-cell lymphomas. As previously described, the immune system has an enormous number of possible permutations, making shared idiotopes highly unlikely. Applicant has found 32 antiidiotype antibodies capable of cross-reacting with B-cell lymphomas from 108 different patients. This data shows the potential also exists for therapy against B-cell lymphomas generally using a panel of anti-idiotype antibodies. In fact, applicant has isolated one anti-idiotype, S37-48-6-2-6, that is capable of cross-reacting with B-cell lymphomas in 15 out of 381 patients.
  • Yet another aspect of the present invention is the use of these anti-idiotypes to shared idiotopes in immuno- therapeutic treatment of B-cell lymphomas.
  • a panel of anti-idiotypes reactive to shared idiotopes can be generated, from which one or more antibodies may be used to treat a patient; this therapeutic modality address many of the problems in the prior art, which have been previously discussed.
  • These novel antibodies have advantages over private anti ⁇ idiotypes in that they are more economical and practical to use in disease, treatment, diagnosis and/or monitoring.
  • Applicant has also discovered that AIDS-associated B-cell lymphomas express antibodies that may be useful in active and/or passive treatment of HIV infection. Applicant has discovered that antibodies produced by these lymphomas recognize HIV antigens.
  • the lymphoma cells can be induced, for example, by hybridoma techniques to secrete these antibodies. Antibodies so generated can then be used as passive therapy to treat HIV infection. Applicant has ' generated cell lines from such AIDS- associated lymphomas, the cells of which secrete human monoclonal antibodies reactive with the HIV virus. Applicant has isolated and tested one of these antibodies and have found that it reacts immunologically with the envelope glycoprotein antigen of HIV virus (gp 120) . Thus, these B-cell lymphomas are a source of antibodies that react with HIV virus. Since they were derived from human monoclonal tumors, such antibodies are preferred for certain applications over the mouse monoclonal antibodies frequently employed in therapy. These human antibodies can also be used to detect and identify the HIV virus.
  • anti-idiotype antibodies These antibodies produced from AIDS-associated lymphomas also can be used to produce anti-idiotype antibodies.
  • the anti-idiotypes bear the "internal image," i.e.. share certain three dimensional features with the original antigen to which the antibodies bind.
  • these anti-idiotypes immunologically mimic the HIV antigens. They are readily available and non-toxic to humans and can elicit an immune response in the same manner as the corresponding epitopes of the original antigens without the accompanying viral threat to the patient. This immune response can act to protect the patient from infection by the real virus.
  • judiciously mixing various antiidiotypes a broad immune response can be invoked in a patient that will react to many variants of the HIV virus.
  • proteins with which the anti-shared idiotypes react include: anti-DNA autoantibodies typically associated with systemic lupus erythematosus ("SLE”) ; rheumatoid factor ("RF"), an autoantibody typically associated with rheuma ⁇ toid arthritis; and anti-nuclear proteins autoantibodies typically associated with Sjogren's syndrome.
  • a preferred embodiment of the present invention is the L50- 19 anti -shared idiotope antibody, which is cross-reactive with RF and the 16.6 autoantibody associated with SLE.
  • this anti-idiotype antibody it has been shown by the applicant that RFs in some patients have restricted idiotypes.
  • the L50- 19 antibody is useful in passive immunotherapy to modulate or deregulate the production of pathogenic autoantibodies, e.g.. 16.6 and RF.
  • solid phase immuno- adsorbent devices incorporating L50-19 are useful in extracorporeal extraction of autoantibodies from patient plasma.
  • the L50-19 antibody is useful for in vitro assays useful for diagnosis, prognosis and monitor ⁇ ing of autoimmune disease, wherein the L50-19 functions as the detector of autoantibodies.
  • Hybridomas produced as described immediately above, from HIV associated lymphomas were grown in tissue cul ⁇ ture.
  • Supernatants containing the secreted idiotype were tested for HIV binding activity by Western blotting.
  • Western blotting was performed by incubating the super ⁇ natants with cell lysates derived from an ⁇ anti-HIV infected cell line known as H9/HTLV-IIIB (ATCC Designation CRL 8543) , according to the following protocol. Extracts from H9/HTLV-IIIB cells were prepared by disrupting eighty million cells with one ml of viral disruption buffer (0.1% Triton-X 100 in PBS, pH 7.2, and .15 mg. diethylthio- threitol/ml) .
  • the lysate was clarified by centrifugation for 10 minutes at 12,000g.
  • the supernatant was mixed 1:1 with 2X sample buffer and 0.4ml of this mixture was fractionated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (hereinafter referred to as SDSPAGE) on a 14% slab gel.
  • SDSPAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis
  • the blot was incubated overnight at 40C in blocking buffer containing 20% calf serum in PBS, pH 7.2. After blocking, the nitrocellulose sheet was placed onto slot blot apparatus (Integrated Separation Systems, Park, MA) and aligned with the channels of the blotter.
  • Antibodies were characterized further by testing hybridoma supernatants for reactivity against frozen tis- sue sections of the patient's tumor tissue and unrelated human tonsil using an immunoperoxidase staining technique. (See Thielmans, K. , et al.. J. Immunol. 133:495 (1984).) Anti-idiotypes were selected on the basis of reactivity with both the patient's idiotype and tumor tissue, but not with the panel of isotype matched immunoglobulins or ton ⁇ sil (from unrelated donor) . The anti-idiotype secreting hybridomas were then cloned by limiting dilution and expanded by in vitro passage. Culture supernatants or purified antibody obtained were utilized in subsequent studies.
  • a competitive inhibition ELISA was employed as the primary screen to identify anti-idiotypes that showed detectable binding to immunoglobulin in normal human serum.
  • Anti-idiotypes were diluted serially and mixed with either undiluted normal human serum (pooled from 40 normal donors) or horse serum as a control. After one hour, samples were added to a microtiter plate, previously coated with the tumor idiotype, and incubated for an addi ⁇ tional hour. Plates were washed and horseradish peroxi- dase conjugated goat anti-mouse immunoglobulin G (Tago Inc. , Burlingame CA) was added.
  • Bound anti-idiotype was measured by adding ABTS-hydrogen peroxide substrate, and the absorbance was measured at 405 nm by an automated ELISA plate reader. Binding to normal human serum immuno- globulin was considered significant when there was a fourfold or greater inhibition of anti-idiotype reactivity with the tumor immunoglobulin by pooled human serum compared to control horse serum. A second screening assay was employed to quantitate the level of the shared idiotope in normal human serum. Saturating concentrations of anti-idiotypes identified by the primary screen were incubated with a range of concen ⁇ trations of purified tumor idiotype and with serial dilu- tions of pooled normal human serum.
  • Antibodies to shared idiotopes were tested for reactivity with lymphomas nd benign hyperplastic lymphoid tissues (tonsil or lymph node) by immunofluorescence and/or immunoperoxidase staining of fresh frozen cryostat sections or cell suspensions.
  • lymphomas nd benign hyperplastic lymphoid tissues tonsil or lymph node
  • Immunofluorescence staining of cell suspensions was analyzed either by fluorescence microscopy or flow cytometry using a fluorescence activated cell sorter (FACS 440, Becton Dickinson, Mountain View, CA) .
  • Immunoglobu ⁇ lin expression was determined by staining with fluores- cein conjugated, goat anti-immunoglobulin heavy or light chain reagents (Tago) .
  • Idiotype expression was determined by indirect immunofluorescence staining using a fluores- cein conjugated, goat anti-mouse immunoglobulin (Tago) reagent in a second step.
  • One to five anti-idiotypes were developed for each of 67 B-cell lymphoma patients.
  • One hundred ninety-nine (199) monoclonal antibodies were reduced from over 60 fusions (Table 1) . These monoclonal antibodies were specific for the immunizing idiotype and were non-reactive with a panel of six other lymphoma-derived idiotypes.
  • the 199 monoclonal antibodies were selected both because of their idiotypic specificity and comprehensive reactivity with the tumor cell population in the patient's biopsy specimen.
  • the initial screening assay was designed to identify anti-idiotypes that cross-reacted with normal human serum.
  • a representative assay is shown Figure 1 using the anti- idiotype designated C33 -13-8.
  • Undiluted normal human serum (but not the horse serum control) was able to inhibit the binding of anti-idiotype to its corresponding shared idiotope on the tumor idiotype.
  • An anti-idiotype reactive with a private determinant present on this tumor idiotype was not inhibited by either human or horse serum. Data not shown) .
  • 152 anti-idiotypes 76%) were found to completely non-reactive with pooled normal human serum.
  • Such anti-idiotypes recognize private determinants expressed on the corresponding patient's lymphoma that are not present in pooled normal serum.
  • Forty-seven of the 199 MAbs (24%) were found to react with 22 shared idiotopes present in pooled normal human serum immunoglobulin. (Table 1) .
  • Applicant has found that 12 of 15 tested AIDS associ- ated lymphomas react with five anti-idiotype antibodies. These anti-idiotypes have been deposited with the ATCC, Rockville, MD, under accession numbers: S2-33 - 8, ATCC # HB9973; L50-19-13, ATCC # 9977; S30-47-9, ATCC # HB9980; B4-11-2, ATCC # 9984; S37-48-6-2-6, ATCC # HB10009. Applicant also has deposited the patient idiotype produc ⁇ ing hybridoma pairs that were used to select hybridomas producing anti-idiotypes reacting with shared idiotopes.
  • 52-33-8 is reactive with idiotype from H21-12 (ATCC #HB9955) and 7112-14 (ATCC #9953).
  • S2-33-8 is the best antibody that has been identified as reactive with shared idiotopes expressed by AIDS-associated B-cell lymphomas since it reacts with up to 50% of the cases (unpublished results) .
  • the reactivity of these anti ⁇ idiotypes with AIDS-associated and non-AIDS associated lymphomas are set forth below.
  • Applicant's results are unexpected because of the enormous number of different B-cells within the body. Applicant's result suggests that AIDS lymphoma B-cells might react with a common antigen.
  • the idiotype from one of these cases was isolated and examined for reactivity with HIV. This idiotype was found to react with the HIV envelope glyco-protein (gp 120) . Since the cell line producing this idiotype may be cloned and expanded in vitro, it Is a source for human monoclonal anti-HIV antibody.
  • This human monoclonal antibody has several advantages over other types of antibodies that may be raised to HIV. For example, mouse monoclonal antibodies may be produced to HIV virus. However, these will suffer from several problems when used in vivo for immunotherapy of HIV infection.
  • mouse mono ⁇ clonal antibodies for therapy will be their immunogenic- ity, as they elicit anti-mouse antibody responses in humans. Once a human anti-mouse antibody response has occurred, therapeutic effectiveness of the administered antibody is eliminated.
  • a human monoclonal antibody would be far less immunogenic and would not result in any neu ⁇ tralizing antibodies produced by the host.
  • human antibodies are capable of mediating other host effector mechanisms that are not mediated by mouse mono ⁇ clonal antibodies such as the ability to fix human comple ⁇ ment or mediate antibody dependent cell mediated cytoxicity.
  • Such antibodies may be administered passively to treat established HIV infection, as has been done recently by Jackson, gt al.. The Lancet Sept. 17, 1988:647 (1988) , using immune serum derived from HIV sero-positive asymptomatic individuals, or to prevent sero conversion in an individual exposed to HIV.
  • Other uses for human mono ⁇ clonal antibodies reactive with HIV include passive immunotherapy in patients who recently have been exposed or infected with HIV as a means of preventing disease.
  • These anti-HIV monoclonal antibodies may also be used for production of anti-idiotype antibodies.
  • Anti-idiotype antibodies may be produced that mimic epitopes on the
  • SUBSTITUTE SHEET corresponding HIV antigens Such anti-idiotypes may be used in active immunotherapy to stimulate anti-HIV immune responses. These antiidiotypes may be formulated with carrier proteins and immunologic adjuvants to augment antibody responses reactive with HIV.
  • monoclonal anti-HIV anti ⁇ bodies in passive immunotherapy are described below.
  • Levels of anti-HIV antibody in the plasma could be monitored to adjust the dosage and frequency of administration to achieve persistent circulating anti-HIV antibody and simultaneously measure HIV antigens, looking for disap ⁇ pearance of viral proteins.
  • Doses of anti-HIV antibody could be repeatedly given to achieve persistent antibody excess and penetration into HIV infected tissues. Such osage regimens could be applied over a period of weeks or months in either patients with established infection or those who have recently been exposed to HIV.
  • anti-HIV monoclonal antibodies isolated from AIDS lymphoma cells an be used as immunogens to generate "internal image" anti-idiotype antibodies.
  • Such anti- idiotypes can be produced in mice using established hybridoma techniques. These internal image anti-idiotypes could be covalently linked to carrier proteins and used with immunological adjuvants to boost immune responses. 0.5 to 10 mg of antiidiotype could e given subcutaneously or intramuscularly.
  • Such patients after repeated immuni ⁇ zations would produce neutralizing immunoglobulins that would be similar to anti-HIV antibodies produced by some individuals upon exposure to HIV.
  • These anti-idiotype vaccines or immunotherapeutic gents would have a role in prevention of HIV infection and/or treatment established disease, respectively.
  • anti-idiotype antibodies directed against AIDS B-cell lymphoma idiotypes involve passive immunotherapy of B-cell lymphomas that arise in these patients. Doses up to 500 mgs could be given intravenously over up to several hours achieving antibody excess and penetration of antiidiotype into lymphoma tissue. Penetration of anti-idiotype into tissue has been associated with tumor responses in other types of human B-cell lymphomas. Because of the availability of preexisting anti ⁇ idiotypes for these patients, one can use anti-idiotypes earlier in the treatment course, as the necessity of making a customized anti-idiotype has been eliminated.
  • tumor cells from patients with HIV or non-HIV associated lymphoma would be tested for reactivity with this panel of antibodies using either immunofluorescence or immunohistochemistry as described in applicant's methods section.
  • the antibody or antibodies found to be reactive with the lymphoma could be used in diagnosis, monitoring ind/or treatment.
  • the best antibody or antibodies for administration to any patient from the panel herein disclosed and claimed an only be determined by individualized testing, for example immunofluorescence or immunohistochemistry (see above) , or by methods previ ⁇ ously described (see Meeker, T. et al.. Blood 65:1349 (1985) ) ; or methods known to those skilled in the art.
  • Table 2 also shows the reactivity of each anti- idiotype with follicular hyperplasia tissue.
  • Follicular hyperplasia is a description for the histologic appearance of lymph nodes that are being stimulated by foreign anti- gen. For at least 28 of the anti-idiotypes, no reactivity with these tissues was seen.
  • the other 16 monoclonal antibodies reacted with a small percentage 5%) of cells in the hyperplastic lymphoid tissue, i.e.. rare isolated cells were seen to react with the monoclonal antibody.
  • Figure 3 shows an example of the reactivity with occasional cells as seen with antibody C33-3-8.
  • the 32 Anti-idiotypes reactive with shared idiotopes identified 32 distinct determinants (idiotopes) since each of these anti-idiotypes recognized a different group of lymphomas.
  • These anti-idiotypes have been-deposited with the ATCC, Rockville, MD, having the following accession numbers: L50-5-14, ATCC #HB9973; H27-17-11, ATCC #HB9978; H48-16, ATCC #HB9979; S37-48-6-2-6, ATCC #HB 10009; H28- 48-11, ATCC #HB9957; L46-49-10-3, ATCC #HB9958; S2-33-8, ATCC #HB9981; L50-19-13, ATCC #HB9977; S30-47-9; ATCC #HB9980; B4-11-2, ATCC #HB9984; B4-1-2-31, ATCC #HB9974; C33-13-8, ATCC #HB9985; C31-145-12, ATCC #HB9983; H22-10- 11, ATCC #HB9982; C39-25-25
  • FSC follicular, small cleaved cell
  • SNC small, non-cleaved cell
  • DSC small cleaved cell type, diffuse
  • SCL small cell (CLL)
  • DLC large cell type, diffuse.
  • Table 5 summarizes the expression of shared idiotopes by the various histologic subtypes of non-HIV associated B-cell lymphomas.
  • the shared idiotopes defined by these monoclonal antibodies do not appear to be restricted to a particular histologic subtypes of lymphoma.
  • the number of cases that are not follicular small cleaved cell lymphomas is small there is a suggestion that the differ- ent histologic subtypes vary in their frequency of expres ⁇ sion of shared idiotopes.
  • 20 different anti-idiotypes recognized 30% of follicular small cleaved cell lymphoma idiotypes.
  • follicular lymphomas also express shared idiotopes, but much less frequently than seen in CLL or AIDS associ ⁇ ated lymphomas.
  • Applicant identified multiple shared idiotopes but each one is expressed in low frequency in the follicular lymphoma population (Table 2) .
  • the follicular lymphoma shared idiotopes do not appear to be associated with any immunoglobulin heavy or light chain type.
  • these lymphomas may be grouped into families based on heir shared idiotope expression.
  • an impor ⁇ tant reason for tumor escape from therapy with anti- idiotypes is related to selection of idiotype negative, immunoglobulin positive variant cells. These cells arise because of extensive somatic mutation of immunoglobulin variable region genes Meeker, T. et al.. New Eng. J. of Med. 312:165 8 (1985)). It is possible that shared idio- topes may not mutate as frequently as other segments within he variable region. This has been shown to be the case for the Vk Illb gene of CLL Kipps T.J., et al.. J. EXP. Med. 167:840 (1988). If shared idiotopes do not mutate as readily as other idiotopes then therapy with anti-idiotypes reactive with these determinants may be more effective.
  • Anti-idiotypes to shared idiotopes may be generated and selected using he techniques described herein. Large numbers of anti-idiotypes must be generated in order to find those that identify shared idiotopes. Moreover, therapeutically useful anti-idiotypes must meet certain other criteria to be useful in vivo. For example, the
  • SUBS amount of cross-reactive idiotope present in serum must be less than 50 g/ml in order for administered anti-idiotype to achieve penetration into tissues (see Meeker, et al.. Blood 65:1349 (1985)).
  • Another important factor is the proportion of cells within the tumor expressing the shared idiotope and reacting with the shared anti-idiotype. Applicant has purposely selected anti-idiotypes reacting with a high proportion (>85%) of the cells in the tumor since immunotherapy is applicant's major objective.
  • Autoantibodies e.g.. anti-DNA and RF antibodies
  • Autoantibodies are then tested for reactivity with the applicant's panel of ink-shared idiotype antibodies using conventional ELISA techniques. Briefly, the anti- idiotype antibody is used to coat a microtiter plate. The autoantibody or control antibodies are then added to the wells at various dilutions. After washing the wells, enzyme labeled anti-id is added to the Yells to detect the bound autoantibody.
  • the anti-shared idiotype antibodies discovered by the applicant are listed n Table 6. The clinical correlation of the L50-19 idiotype level in rheumatoid arthritis and the disease progression and remission are depicted in Figures 5-7.
  • a method for the in vitro detection of the presence of an auto ⁇ antibody includes contacting a fluid sample obtained from a patient with at least one anti-idiotype antibody having specific reactivity with an autoantibody, and determining the co plexing of the anti-idiotype antibody to auto ⁇ antibodies of the fluid sample by means of an immunoassay.
  • a quantitative measurement of the amount of autoantibody in a fluid sample may be made by an in vitro method including contacting the fluid sample with at least one anti-idiotype antibody having specific reactivity with autoantibody, determining the amount of the anti-idiotype antibody associated with the autoantibody, and correlating the amount of the association with the amount of auto- antibody present in the sample.
  • the presence or amount of anti-idiotype antibodies associated with the autoantibody being detected can be achieved by labeling the anti-idiotype antibody with a marker that is capable of being detected.
  • the labeled antibody used in the present invention may be provided with the same labels used in prior art immunoassays. Among these may be mentioned fluorogenic labels for detection by fluorometry, as described in U.S. Patent No. 3,940,475, and enzymatic markers, as described in U.S. Patent No. 3,645,090.
  • the label may also be a radio- isotope, such as I- 25, using, for example, the procedure of Hunter and Greenwood, Nature, 144:945 (1962), or that of David, et al.. Biochemistry, 13:1014-1021 (1974).
  • the label may be biotin, which may be detected by its interaction with an enzymatically labeled avidin.
  • biotin an enzymatically labeled avidin.
  • the assay methods of the present invention may be qualitative or quantitative in nature and may be employed to monitor patients undergoing therapy or in initial diagnosis of autoimmune disease.
  • autoantibodies are prefer- ably detected in fluid samples, they also may be deter ⁇ mined in tissue samples. Fluid samples utilized according to the present invention include whole blood, serum, plasma, urine, sweat, tears and saliva.
  • a diagnostic kit for detecting the presence or amount of autoantibodies, which includes at least one anti-idiotype specific for the autoantibody of interest, may be assembled.
  • step C. I. Using a multichannel pipette, deliver lOO ⁇ L of the anti-shared idiotype antibody to the wells where the test samples were reacted.
  • K. Prepare a 1:1000 dilution of Horseradish peroxidase conjugated Avidin(TAGO) in dilution buffer.
  • step J. O. Prepare a IX dilution of ABTS(2,2'-Azino-bix(3- ethylbenthiazoline-6-sulfonic acid) , Diammonium Salt, Sigma Chemical.
  • the L50-19 antibody is covalently coupled to a solid phase, support such as sepharose, cellulose or polyacryl- amide, or others. Patients with active disease and a rising concentration of the L50-19 reactive idiotype in the plasma would be eligible for extracorporeal therapy. Blood or plasma is continuously passed over the solid phase immunoadsorption device which will remove L50-19 reactive idiotype from the plasma. Adsorbed plasma nay be re-infused into the patient or discarded and replaced by normal plasma. One or more total plasma volume exchanges should remove a majority of the disease asso ⁇ ciated idiotype.
  • the treatment is repeated at intervals ranging from 1 day to monthly until either the idiotype is educed to a level which is at or below the concentration seen when disease is inactive or disease remission occurs.
  • the idiotype level is monitored and re-treatment may be initiated when the idiotype level rises and disease pro- gressing occurs. Removal of pathogenic auto-antibodies from plasma prevents the buildup of these antibodies in tissues and reduces the severity of disease.

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Abstract

Des lymphomes de cellule B expriment l'immunoglobuline de surface (immunoglobuline) contenant des déterminants idiotypiques (idiotypes) qui peuvent être exploités comme marqueurs spécifiques de tumeur. On a produit des anticorps monoclonaux murins (MAbs) réagissant avec le marqueur idiotype dérivé de 67 patients avec des lymphomes cellulaires clivés petits, folliculaires de faible grade. Sur 199 anticorps monoclonaux, 47 (24 %) ont réagi avec l'immunoglobuline de sérum humain normal échantillonné dans des concentrations allant de 0,6 νg/ml à 160 νg/ml. De ces 40 anticorps monoclonaux, 90 % ont eu une réaction croisée avec l'idiotype présent dans du sérum normal à des niveaux inférieurs à 50 νg/ml. 32 de ces anti-idiotypes ont été envoyés contre un idiotope partagé exprimé sur des cellules de lymphomes d'un autre patient. La fréquence d'expression de l'idiotope partagé définie par chaque anticorps était comprise entre 0,26 % et 3,9 % des lymphomes B-cellulaires testés. Un groupe de 5 anticorps anti-idiotypes ont réagi avec 80 5 de lymphomes associés au SIDA. En se basant sur la réactivité de ces anticorps monoclonaux, des tumeurs ont pu être groupées en familles distinctes. En aggrégat, ces 32 anticorps monoclonaux ont réagi avec un total de 108 des 332 cas de lymphomes B-cellulaires (32,5 %), y compris 35 des 116 lymphomes cellulaires folliculaires clivés petits (30 %). Nombre de ces idiotopes anti-partagés ont réagi avec plus d'un sous-type istopathologique de lymphome. Des anti-idiotypes ont été utilisés dans le diagnostic et la thérapie du lymphome B-cellulaire. De plus, on a découvert au moins 7 anticorps idiotypes anti-partagés qui ont réagi avec des auto-anticorps, par exemple 16,6 et RF. Le développement d'une librairie d'anti-idiotypes réagissant avec des idiotopes partagés devrait faciliter ces études cliniques en évitant le besoin de développer un hybridome personnalisé pour chaque patient.
PCT/US1990/000424 1989-01-31 1990-01-31 Anticorps anti-idiotypes reagissant avec des idiotopes partages exprimes par des lymphomes humains et des auto-anticorps Ceased WO1990008779A1 (fr)

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Cited By (4)

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GR900100845A (en) * 1990-01-22 1992-06-25 Idec Pharma Corp Anti-idiotype antibodies reactive with shared idiotopes expressed by human lymphomas and autoantibodies
WO1994027151A1 (fr) * 1993-05-19 1994-11-24 Michel Geffard Utilisation de molecules reconnues par des autoanticorps de serums humains pour le diagnostic ou le traitement du sida
US7118741B1 (en) 1995-05-12 2006-10-10 The National Blood Authority Transepithelial transport of molecular species
ITRM20100441A1 (it) * 2010-08-05 2012-02-06 Michele Pitaro Procedimento per la produzione di anticorpi monoclonali anti-idiotipo ad uso diagnostico e/o terapeutico

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PT90582B (pt) * 1988-05-17 1994-09-30 Soldano Ferrone Anticorpos anti-idiotipo destinados a antigenios associados a melanomas anti- -humanos de elevado peso molecular

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR900100845A (en) * 1990-01-22 1992-06-25 Idec Pharma Corp Anti-idiotype antibodies reactive with shared idiotopes expressed by human lymphomas and autoantibodies
WO1994027151A1 (fr) * 1993-05-19 1994-11-24 Michel Geffard Utilisation de molecules reconnues par des autoanticorps de serums humains pour le diagnostic ou le traitement du sida
FR2705234A1 (fr) * 1993-05-19 1994-11-25 Geffard Michel Utilisation de molécules reconnues par des autoanticorps de sérums humains pour le diagnostic ou le traitement du SIDA.
US7118741B1 (en) 1995-05-12 2006-10-10 The National Blood Authority Transepithelial transport of molecular species
ITRM20100441A1 (it) * 2010-08-05 2012-02-06 Michele Pitaro Procedimento per la produzione di anticorpi monoclonali anti-idiotipo ad uso diagnostico e/o terapeutico
WO2012017472A1 (fr) 2010-08-05 2012-02-09 Michele Pitaro Procédé de production d'anticorps monoclonaux anti-idiotypiques à des fins diagnostiques et/ou thérapeutiques

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