WO1991001752A1 - Anticorps monoclonaux immunosuppresseurs, hybridomes et procedes de transplantation - Google Patents

Anticorps monoclonaux immunosuppresseurs, hybridomes et procedes de transplantation Download PDF

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Publication number
WO1991001752A1
WO1991001752A1 PCT/US1990/004215 US9004215W WO9101752A1 WO 1991001752 A1 WO1991001752 A1 WO 1991001752A1 US 9004215 W US9004215 W US 9004215W WO 9101752 A1 WO9101752 A1 WO 9101752A1
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Prior art keywords
hybridoma
reactive
monoclonal antibody
antibody
cells
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PCT/US1990/004215
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English (en)
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John A. Hansen
Paul J. Martin
Claudio Anasetti
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Fred Hutchinson Cancer Research Center
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Publication of WO1991001752A1 publication Critical patent/WO1991001752A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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
    • C07K16/2809—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 against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to new monoclonal antibodies having specificity for the CD3-T cell antigen receptor complex, to hybridomas for producing the monoclonal antibodies, and to therapeutic methods and compositions employing the antibodies.
  • graft-versus-host disease Recipients of allogeneic organ or tissue transplants are routinely treated with immunosuppressive agents to prevent graft rejection and, in the case of bone marrow transplantation, to prevent immunocompetent lymphoid cells from causing graft-versus-host disease (GVHD).
  • Drugs used to control rejection or GVHD such as corticosteroids, azathioprine, methotrexate, cyclosporine and antithymocyte globulin, have been shown to have broadly suppressive effects on eell mediated immune function.
  • GVHD graft-versus-host disease
  • EBV-LPS Epstein-Barr virus-associated lymphoproliferative syndromes
  • Latent EBV infection, together with impaired immune responses, chronic antigenic stimulation by the allograft and direct oncogenic effects of immunosuppressive drugs may represent factors that increase the incidence of EBV-related disease after organ grafting. Severe GVHD, immunosuppressive treatment, HLA incompatibility between donor and recipient and T cell depletion of the donor marrow have been suggested as possible risk factors for the incidence of EBV-LPS in bone marrow transplant recipients.
  • OKT3 is a murine monoclonal antibody of IgG2a isotype specific for the CD3-T cell antigen receptor complex (see U.S. Patents Nos. 4,361,549, 4,515,893, and 4,654,210). Martin et al., Transplantation Proceedings, Vol. XVI, No. 6, pp. 1494-1495, 1984, and Remlinger et al., Human Immunology, Vol. 9, pp.
  • 21-35 (1984) disclose the use of murine IgG2a m ⁇ ___elonal antibodies 9.6 (anti-CD2), 10.2 (anti-CD5), 12.1 (anti- CD6), 35.1 (anti-CD2), and 64.1 (anti-CD3) in the treatment of acute graft-versus- host disease.
  • anti-CD3 murine IgG2a monoclonal antibodies, including OKT3 has been associated with acute side effects, including pyrexia, chills, dyspnea, chest pain, vomiting, wheezing, nausea, diarrhea, tremor, and increased susceptibility to cytomegalovirus and herpes simplex infection.
  • murine IgG2a anti-CD3 monoclonal antibodies specifically antibody 64.1
  • an immunosuppressive agent for the treatment of acute GVHD has been documented to be associated with a substantial risk of EBV-associated lymphoproliferative disorders (see Martin et al., Annals of Internal Medicine, Vol. 101, pp. 310-315, 1984 and Martin et al., American Journal of Kidney Diseases, Vol. XI, No. 2, pp. 149-152, Feb. 1988.
  • EBV-associated lymphoproliferative disorders have similarly been associated with administration of the OKT3 antibody.
  • the EBV-related lymphoproliferative syndrome has emerged as a major complication in attempts to treat graft rejection and acute GVHD with monoclonal antibodies.
  • monoclonal antibodies particularly with the IgG2a anti-CD3 monoclonal antibodies OKT3 and 64.1, a major need exists for improved monoclonal antibodies which are effective as immunosuppressive agents, but which are not associated with acute toxicity and do not enhance the risk of B-cell proliferation and transformation.
  • the antibodies are effective as immunosuppressive agents when administered in vivo, but are not pyrogenic, do not induce respiratory distress, and do not increase the risk of EBV-related lymphoproliferative syndrome. Accordingly, the antibodies are effective in the treatment or prophylaxis of organ or bone marrow rejection by a transplant recipient, in the treatment or prophylaxis of graft-versus-host disease, or for diagnostics purposes.
  • Preferred antibodies of the invention are murine monoclonal antibodies of the IgG2b isotype which do not interact with Fc receptors on human monocytes.
  • a representative embodiment of the invention is the hybridoma designated BC3 which produces a monoclonal antibody, also designated BC3.
  • the hybridoma BC3 has been deposited with the American Type Culture Collection, 12301 Park Lawn Drive, Rockville, Maryland 20852, and assigned the ATCC accession No. HB 10166.
  • FIGURE 1 is a graphic representation of the comodulation of the epitopes on peripheral blood lymphocytes bound by either antibody 64.1 or antibody BC3, demonstrated by staining with either FITC-conjugated antibody BC3 or FITC- conjugated antibody 64.1, respectively.
  • FIGURE 2 is a graphic representation of cell proliferation of peripheral blood mononuclear cells induced by antibody BC3 or antibody 64.1, as measured by thymidine incorporation assay.
  • FIGURE 3 is a graphic representation of cell proliferation of peripheral blood mononuclear cells induced by an alloantigen in the presence of antibody BC3, as measured by thymidine incorporation assay.
  • the term "monoclonal antibody” means an antibody composition having a homogenous antibody population. It is not intended to be limited as to the source of the antibody or the manner in which it is made.
  • the term “functional equivalent” means a monoclonal antibody having selective binding affinity for the CD3-T antigen receptor complex of human T lymphocytes (T cells) and whieh does not bind to human monocyte Fc receptors.
  • the term “progeny” is intended to include all derivatives, issue, and offspring of the parent hybridoma that produce the monoclonal antibody of the parent or a functional equivalent thereof, regardless of generation of karyotic identity.
  • Antibodies of the invention specifically bind the T l9-29 antigen of the CD3 differentiation cluster of human T lymphocytes as defined in Bernard et al. (Eds.), in Joint Report of the First International Workshop on Leukocyte Differentiation
  • CD3 monoclonal antibodies OKT3 and 64.1 CD3 monoclonal antibodies OKT3 and 64.1, however, the antibodies of the invention are of the IgG2b isotype and do not interact with Fc receptors on human monocytes (see Kfenneth et al., European Journal of Immunology, Vol. 16, pp. 478-486, 1986). Accordingly, the in vivo administration of the monoclonal antibodies of the invention does not result in the inducement of EBV-related lymphoproliferative syndrome, febrile reactions, bronchospasm or hypotension typically present after administration of the IgG2a anti-CD3 monoclonal antibodies OKT3 ind 64.1, complications which are believed to result from the secretion of lymphokines after antibody binding to T cells crosslinks to Fc receptor position accessory cells.
  • a presently particularly preferred, representative embodiment of the antibodies of the invention is the antibody BC3 produced by the BC3 hybridoma (ATCC No. HB 10166) and functional equivalents thereof.
  • Antibody-producing lymphocytes used as fusion partners to make the hybridomas of the invention may be generated by immunizing mice, such as BALB/c mice, with PHA activated T cells or membrane extracts made therefrom.
  • the mice are preferably innoculated intraperitoneally with an immunogenic amount of the cells or extract and then preferably boosted with similar amounts of the immunogen over a period of about 10 days to two weeks.
  • Spleens may be collected from the immunized mice after the final booster injection and processed to obtain a cell suspension for use in fusion with myeloma cells.
  • Myeloma cells used as fusion partners to make the hybridomas of the invention are well known and readily available in the art.
  • BALB/c MOPC21 NS1/1 is used as the myeloma fusion partner, although other myeloma cell lines may be used for this purpose.
  • the spleen cells from immunized mice are combined with the myeloma cell fusion partners in the presence of a suitable fusion agent, such as polyethylene glycol. After fusion, the cells are separated from the fusion medium and grown in a selective medium, such as HAT medium, to eliminate nonhybridized parent cells. Supernates from the remaining hybridomas are screened for specific binding affinity for the CD3-T cell antigen receptor complex of human peripheral T cells and lack of binding affinity for human monocytes by conventional assay procedures, such as by radioimmunoassay, enzyme immunoassay, fluorescence immunoassay, or the like.
  • hybridomas of interest may be selected by screening supernates for blocking the binding of a fluorescence in isothiocyanate (FITC) conjugated anti-CD3 antibody by using flow microfluorimetry.
  • FITC fluorescence in isothiocyanate
  • 0.5 x 10 peripheral blood mononuclear cells obtained from volunteers and purified by density gradient centrifugation on Ficoll Hypaque (S.g. 1077) may be incubated with 50 ⁇ l of hybridoma culture supernates for 30 min. at 4°C in the presence of 0.1% sodium azide. Cells may then be incubated with saturating concentration of a known CD3-specific antibody conjugated to FITC. Incubation may be carried out for 30 min. at 4°C in the presence of 0.1% sodium azide.
  • cells may be evaluated by flow microfluorimetry. Green fluorescence intensity of samples preincubated with hybridoma supernates may be compared to green fluorescence intensity of samples preincubated with medium. Hybridoma supernates capable of reducing the fluorescence intensity of cells stained with FITC-conjugated CD3 antibody should contain an antibody specific for the CD3 antigen. Supernates found to contain a CD3 antibody may be further screened for the presence of antibodies of the desired IgG2b isotype as follows.
  • 50 yl of hybridoma supernate containing the newly found anti-CD3 antibody may be incubated with 0.5 x 10 unfractionated peripheral blood mononuclear cells in 200 ⁇ l round bottom well plates for 72 hours at 37°C in the presence of 5% CO « atmosphere.
  • Induction of DNA synthesis may be measured by incorporation of tritiated thymidine. Since antibodies of IgG2a, IgGl and IgG3 isotype are known to be mitogenic for unfractionated peripheral blood mononuclear eells, supernates containing antibodies inducing DNA synthesis are discarded.
  • Supernates containing anti-CD3 antibodies not inducing DNA synthesis may contain antibodies of the IgG2b or the IgM isotype.
  • Anti-CD3 antibodies of the IgG2b isotype may then be identified by various conventional means known in the art, such as by ELISA (enzyme-linked immunosorbent assay) or double immunod ⁇ f fusion, using antibodies or antisera specific for IgG2b antibodies.
  • Hybridomas determined by a suitable screening procedure to produce antibodies of the invention may be grown in vitro in culture medium or in vivo, preferably in the peritoneal cavity of a mouse, using conventional procedures.
  • Monoclonal antibodies of the invention may be separated from the culture medium, or body fluids, such as ascites fluid or serum, and purified by known immunoglobulin jpurification procedures, such as ammonium sulfate precipitation, gel electrophoresis, di-alysis, chromatography and ultrafiltration.
  • Hybridoma BC3 was prepared by fusion of immune murine spleen cells with a murine myeloma cell line, substantially as described by Kohler and Milstein,
  • a BALB/c mouse was immunized intraperitqneally with 2 x 10 _ to 2 x 107 1:1 cell mixture of PHA activated T cells on day 18, day 11 and day 4, before infusion.
  • Spleen cells of the mouse were fused with HGPRT " myeloma cell line BALB/c MOPC21 NS1/1 obtained from Br. Caesar Milstein (Molecular Research Council, Cambridge, England). Selected hybrid cells were subcultured at low density, together with a "feeder cell” suspension of thymocytes from BALB/c mice.
  • hybrid eells at a concentration of 2.5 x 10 /ml and thymocytes at a concentration of 4 x 10 /m9.
  • a 200 ul volume of this suspension was dispensed into microwells, resulting in a seeding of 5 hybrid cells/well.
  • Hybridoma culture supernates were screened, as described above, for anti-CD3 specificity and IgG2b isotype, and cloning of cells from a positive well was performed by limiting dilution (100 hybridoma cells/300 wells) with thymocyte feeder cells as described above, to obtain BC3 hybridoma cells.
  • the hybridoma cells were cultured in RPMI 1640 containing 15% fetal calf serum, 2 mM added glutamine, 1 mM pyruvate, 100 units/ml penicillin, and 1 mg/ml streptomycin. Cultures were maintained at 37°C in a humidified atmosphere containing 5% CO 2 - Cell density was maintained between 0.1 x 10 _ /ml and 0.4 x 10 _ /ml by splitting the cultures every two to three days.
  • BALB/c mice were pretreated with 0.5 ml of intraperitoneal pristane (Alderidge, Milwaukee, WI), and then innoculated by intraperitoneal injection of 5- 10 x 10° BC3 hybridoma cells prepared in accordance with Example 1. After five to 15 days, ascites fluid was obtained by insertion of an 18 gauge needle into the peritoneum and collection by open draining into a sterile 5 ml tube. Fluids were allowed to clot at room temperature for one-half hour, and then centrifuged at 2,500 x G for 10 minutes at 4°C. Multiple ampules of hybridoma cells from ascites fluid of individual selected mice were cryo-preserved in 50% RPMI 1640 medium and 10% DMSO. EXAMPLE 3 - Antibody Purification
  • Ascites fluid obtained according to Example 2 was purified by sequential G-25 Sephadex filtration and affinity chromatography on Protein A-Sepharose CL-4B to obtain purified BC3 monoclonal antibody. All handling of monoclonal antibodies was done with disposable pharmaceutical syringes or other pyrogen-free instruments. Protein A-Sepharose CL-4B columns were stored at 4°C in phosphate-buffered saline (PBS) pH 7.2 containing 0.1% Na azide. Columns were purged with 3 bed volumes of PBS before application of ascites fluid. Where possible, pharmaceutical-grade reagents were employed in preparation of buffers.
  • PBS phosphate-buffered saline
  • Supernate from the BC3 hybridoma of Example 1 contained a murine IgG2b/k antibody, designated BC3, as determined by an ELISA assay using peroxidase- conjugated rabbit anti-mouse Ig isotype specific antibodies.
  • the immunoprecipitate of 1 1 - I surface labeled human PBL lysate with antibody BC3 consisted of a protein complex with a molecular weight of 19-29 kDa by one-dimensional SDS-PAGE. The specificity of BC3 for the CD3 complex was demonstrated by comodulation experiments with the known CD3 antibody 64.1.
  • the BC3 and 64.1 antibodies were further evaluated to characterize their mitogenic properties.
  • Five x 10 peripheral blood mononuclear cells were incubated at 37°C in a 5% CO 2 atmosphere in the presence of 10 ⁇ g of antibody 64.1, antibody BC3 or antibody 9E8 (an irrelevant antibody control).
  • cell proliferation was measured by thymidine incorporation assay, as described in Schooley et al., "T-lymphoeyte subset interactions in the cell- mediated immune response to Epstein-Barr virus.” Cell Immunol., Vol. 86, pp. 402-412, 1984.
  • antibody 64.1 induced cell proliferation, which was maximal on days 3 and 4, whereas antibody BC3 did not induce any cell proliferation.
  • antibody BC3 The effect of antibody BC3 on T cell proliferative response was further characterized as follows. Five x 10 peripheral blood mononuclear cells were incubated with an equal number of HLA-class II, incompatible, irradiated (3000 cGy) peripheral blood mononuclear cells in the presence of 10 ⁇ g/ml of antibody BC3 or 9E8 (an irrelevant antibody control). At various time intervals, cell proliferation was measured by thymidine incorporation assay. As shown in FIG. 3, antibody BC3 completely abrogated cellular proliferative response to alloantigens. EXAMPLE 5
  • BC3 antibody has immunosuppressive properties without the toxicities associated with administration of the other CD3 antibodies.
  • a clinical study was undertaken using escalating doses of BC3 for treatment of patients with acute GVHD refractory to corticosteroids.
  • Ten patients were treated with the antibody.
  • One of 65 infusions was followed by fever and none by other acute reactions.
  • One patient who had been previously treated with ATG subsequently received seven infusions of antibody BC3 for treatment of skin GVHD.
  • a second course of ATG was administered for treatment of recurrent disease. Later, this patient developed a lethal EBV-LPS.
  • the im unosuppressive antibodies of the invention are administered to a patient in therapeutically or prophylactically effective amounts, i.e., amounts sufficient to eliminate or reduce T-cell interaction with transplanted organ or bone marrow tissue in a transplant recipient and thereby reduce or eliminate rejection of the organ or bone marrow transplant.
  • the antibodies will typically be administered parenterally, preferably intravenously, but may be administered by other routes known in the art. Suitable dose and dosage regimens will depend upon the desires of the treating physician, the nature, history and medical condition of the patient, and the specific condition being prophylactically or therapeutically treated.
  • Typical therapeutically or prophylactically effective amounts of antibody for intravenous administration will range from about 0.05 mg/kg/day to about 10 mg/kg/day of patient weight for periods of from about two to about 14 days, or longer.
  • antibodies of the invention will be formulated in unit dosages in injectable form in association with a pharmaceutically acceptable parenteral carrier.
  • suitable, acceptable carriers are typically nontoxic and nontherapeutic. Examples of suitable carriers include saline, Ringer's solution, and human serum albumin solutions.
  • Nonaqueous vehicles such as fixed oils and ethyloleate and liposomes may also be employed. Suitable vehicles may additionally contain minor amounts of additives, such as substances that enhance isotonacity and chemical stability, e.g., buffers and preservatives.
  • Antibody will typically be present in the pharmaceutical carrier for direct administration at final concentrations of from about 0.05 mg/ml to about 5.0 mg/ml.
  • Antibodies of the invention may be administered alone, or in conjunction with other immunosuppressive agents, if desired.
  • Other representative immunosuppressive agents suitable for use in conjunction with the antibodies of the invention include the immunosuppressive monoclonal antibodies, corticosteroids, azathioprine, methotrexate, cyclosporine and antithymocyte globulin. While the invention has' been described in connection with certain presently preferred, illustrative embodiments, it is apparent that various modifications, such as use of the antibodies of the invention for diagnostic or other purposes, can be made by one skilled in the art without departing from the spirit and scope of the invention. Except as precluded by the prior art, any such modifications are intended to be within the scope of the following claims.

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Abstract

Il a été démontré que de nouveaux anticorps monoclonaux présentent une affinité de liaison spécifique au complexe récepteur d'antigène de cellule CD3-T et qu'ils ne réagissent pas avec les monocytes humains. Les anticorps sont immunosuppresseurs et utiles au traitement ou à la prophylaxie du rejet du greffon ou de la réaction du greffon contre l'hôte sans pour autant avoir pour résultat ni des réactions aiguës ni le syndrome lymphoprolifératif associé au virus Epstein-Barr. Des modes de réalisation représentatifs comprennent l'anticorps monoclonal BC3 et l'hybridome BC3 qui sert à produire l'anticorps.
PCT/US1990/004215 1989-07-27 1990-07-26 Anticorps monoclonaux immunosuppresseurs, hybridomes et procedes de transplantation WO1991001752A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019196A1 (fr) * 1992-03-24 1993-09-30 British Technology Group Ltd. ANTICORPS IgG ANTI-CD3 AGLYCOSYLES
US5730979A (en) * 1993-03-05 1998-03-24 Universite Catholique Delouvain LO-CD2a antibody and uses thereof for inhibiting T cell activation and proliferation
US5817311A (en) * 1993-03-05 1998-10-06 Universite Catholique De Louvain Methods of inhibiting T-cell medicated immune responses with LO-CD2a-specific antibodies
US5951983A (en) * 1993-03-05 1999-09-14 Universite Catholique De Louvain Methods of inhibiting T cell mediated immune responses with humanized LO-CD2A-specific antibodies
US6541611B1 (en) 1999-06-18 2003-04-01 Universite Catholique De Louvain LO-CD2b antibody
US6849258B1 (en) 1997-07-18 2005-02-01 Universite Catholique De Louvain LO-CD2a antibody and uses thereof for inhibiting T cell activation and proliferation
US7592006B1 (en) 1993-03-05 2009-09-22 Université Catholique de Louvain Composition comprising the LO-CD2a antibody
US9884921B2 (en) 2014-07-01 2018-02-06 Pfizer Inc. Bispecific heterodimeric diabodies and uses thereof
US10669337B2 (en) 2014-07-25 2020-06-02 Cytomx Therapeutics, Inc. Bispecific anti-CD3 antibodies, bispecific activatable anti-CD3 antibodies, and methods of using the same
US11161906B2 (en) 2013-07-25 2021-11-02 Cytomx Therapeutics, Inc. Multispecific antibodies, multispecific activatable antibodies and methods of using the same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
A.J. MCMICHAEL, "Leucocyte Typing III: White Cell Differtiation Antigens", Published 1987 by OXFORD UNIVERSITY PRESS, see especially pages 932-937. *
A.M. CAMPBELL, "Laboratory Techniques in Biochemistry and Molecular Biology: Monoclonal Antibody Technology", Published 1984 by ELSEVIER, see especially chapters 1, 3, 4, 5, 6 and 8. *
SCAND. J. IMMUNOL., Volume 28, issued 1988, PREIJERS, F.W.M.B. et al., "Human T Lymphocyte Differentiation Antigens as Target for Immunotoxins or Complement-Mediated Cytotoxicity", pages 185-194. *
TRANSPLANTATION, Volume 44, No. 1, issued 1987, FILIPOVICH et al., "Graft-Versus-Host Disease Prevention in Allogeneic Bone Marrow Transplantation from Histocompatible Siblings", pages 62-69. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019196A1 (fr) * 1992-03-24 1993-09-30 British Technology Group Ltd. ANTICORPS IgG ANTI-CD3 AGLYCOSYLES
US5730979A (en) * 1993-03-05 1998-03-24 Universite Catholique Delouvain LO-CD2a antibody and uses thereof for inhibiting T cell activation and proliferation
US5817311A (en) * 1993-03-05 1998-10-06 Universite Catholique De Louvain Methods of inhibiting T-cell medicated immune responses with LO-CD2a-specific antibodies
US5951983A (en) * 1993-03-05 1999-09-14 Universite Catholique De Louvain Methods of inhibiting T cell mediated immune responses with humanized LO-CD2A-specific antibodies
US7592006B1 (en) 1993-03-05 2009-09-22 Université Catholique de Louvain Composition comprising the LO-CD2a antibody
US6849258B1 (en) 1997-07-18 2005-02-01 Universite Catholique De Louvain LO-CD2a antibody and uses thereof for inhibiting T cell activation and proliferation
US6541611B1 (en) 1999-06-18 2003-04-01 Universite Catholique De Louvain LO-CD2b antibody
US11161906B2 (en) 2013-07-25 2021-11-02 Cytomx Therapeutics, Inc. Multispecific antibodies, multispecific activatable antibodies and methods of using the same
US9884921B2 (en) 2014-07-01 2018-02-06 Pfizer Inc. Bispecific heterodimeric diabodies and uses thereof
US10669337B2 (en) 2014-07-25 2020-06-02 Cytomx Therapeutics, Inc. Bispecific anti-CD3 antibodies, bispecific activatable anti-CD3 antibodies, and methods of using the same
US11802158B2 (en) 2014-07-25 2023-10-31 Cytomx Therapeutics, Inc. Bispecific anti-CD3 antibodies, bispecific activatable anti-CD3 antibodies, and methods of using the same

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