Classifications

• • 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
  • C07K16/2839—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 integrin superfamily
  • C07K16/2845—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 integrin superfamily against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • 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
  • C07K16/2821—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 ICAM molecules, e.g. CD50, CD54, CD102
• • 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 the field of transplantation, particularly to methods for preventing allograft rejection.
• alloantigens The antigenic differences between individual members of the same species are referred to as "alloantigens.” When alloantigens are involved in rejection of allogeneic tissue grafts, they are referred to as “histocompatibility antigens.”
• histocompatibility antigens The terms “major histocompatibility antigens” and “major histocompatibility complex” (MHC) refer to the products of a single closely-linked region of genes.
• Graft rejection is the consequence of the host immune response to histocompatibility antigens expressed by the graft tissue. Allografts generally survive for a period of days to weeks, but may subsequently become inflamed and infiltrated with lymphocytes and monocytes. The graft tissue eventually becomes necrotic, and in the case of skin transplants, is sloughed from the skin. However, in the case of a vital organ such as the heart, the sequelae to tissue rejection can be fatal to the recipient. Cyclosporine is a cyclic, nonwater-soluble, highly nonpolar molecule composed of 11 amino acids. Cyclosporine is widely used for prolonging the function of various transplanted organs.
• cyclosporine is somewhat limited, both by its association with infection and also because of hepatic and renal toxicities. Clinical use of cyclosporine is associated with reversible, dose-related increases in blood urea nitrogen (BUN) and serum creatinine levels and depressio of creatinine clearance. Some nephrotoxicity is reported to occur in almost 80% of renal transplant patients using cyclosporine.
• BUN blood urea nitrogen
• lymphocyte function-associated antigen 1 (LFA-1) can be found in Marlin and Springer, Cell 51:813-819 (1987), and Davignon et al. , Proc. Natl. Acad. Sci USA 78:4535-4539 (1981).
• compositions and methods for prolonging the function of transplanted allograft and preventing transplant rejection ar provided.
• the method comprises administering a composition comprising more than one inhibitor of adhesion molecule inhibitor.
• inhibitors of an adhesion molecule an its counter-receptor molecule are utilized.
• the inhibitors include antibodies to adhesion molecules and receptor ligands.
• compositions additionally find use in inflammatory reactions as well as allergies and autoimmune diseases.
• the invention is drawn to compositions and methods for prolonging graft survival in a host.
• the invention provides a means for preventing allograft rejection.
• the compositions comprise adhesion molecule inhibitors.
• adhesion molecule inhibitor is intended a molecule which inhibits the activation of T cells and/or B cells. Such inhibitors act to prevent intercellular adhesion in immunological and inflammatory reactions.
• inhibitors broadly includes molecules which inhibit an adhesion molecule by binding to the adhesion molecule or to a receptor ligands of the adhesion molecule.
• Such inhibitors include, for the most part, antibodies to adhesion molecules or their receptor ligands.
• a variety of cellular adhesion an recognition molecules are known in the art.
• leukocyte integrins for example, LFA-1 (lymphocyte function- associated antigen-1) , Mac-1 (macrophage antigen-1) , VLA-4 (very late antigen-4) , CR3 (complement receptor type-3), CR4 (complement receptor type-4) , LeuM5, and the like.
• LFA-1 lymphocyte function- associated antigen-1
• Mac-1 macrophage antigen-1
• VLA-4 very late antigen-4
• CR3 complement receptor type-3
• CR4 complement receptor type-4
• the cellular adhesion molecules include, for the most part, cell surface glycoproteins that promote intercellular adhesion in immunological and inflammatory reactions.
• Other adhesion or receptor molecules include, for example, LFA-3, ICAM-1, ICAM-2, VCAM-1, ELAM-1, CD-2, pl50,95, and others.
• compositions of the invention comprise more than one inhibitor molecule to the adhesion molecules or receptors.
• the composition include inhibitors to the receptor and the ligand of a receptor- ligand pair (for example, an inhibitor of LFA-1 utilized with an inhibitor of ICAM-1, and an inhibitor of VLA-4 utilized with an inhibitor of VCAM-1) .
• Inhibitors of the invention prevent the adhesion molecules from creating the immune response.
• T cell immune recognition requires adhesion receptors as well as the T cell receptor by promoting attachment of T cells to their targets and transduce regulatory signals to the T cell.
• Inhibitor molecules prevent the activation of antigen receptors on the cell or B cell.
• Preferred inhibitors include antibodies to adhesion receptors or ligands.
• the term "antibodies” include both polyclonal and monoclonal intact molecules as well as fragments thereof, such as, for example. Fab, F(ab) 2 , Fv, which are capable of binding antigen.
• both polyclonal and monoclonal antibodies may be employed in accordance with the present invention.
• antibodies or their functional derivatives, whic are produced in humans or are humanized (i.e., not immunogenic in a human) by recombinant or other technology may be utilized.
• Humanized antibodies may be produced, for example, by replacing an immunogenic portion of an antibody with a corresponding, but not immunogenic, portion (i.e ⁇ chimeric antibodies) .
• Robinson et al. International Patent Publication PCI/US86/02269; Akira et al. , European Patent Application 184,187; Taniguchi, M. , European Patent Application 171,496; Morrison et al.
• the inhibitors are utilized before or after allograft transplantation to prevent rejection.
• the methods of the invention can be utilized with any allograft, either organ or tissue, including but not limited to, heart, kidney, liver, bone marrow cells, skin, and the like.
• compositions of the invention can be administered parenterally by injection, rapid infusion, nasopharyngeal absorption (intranasopharyngeally) , derma absorption, or orally.
• the compositions may alternatively be administered intramuscularly or intravenously.
• Compositions for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
• nonaqueous solvent are poly-propylene, glycol, polyethylene, glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyloleate.
• Carriers or occlusive dressings can be used to increase skin permeability and enhance absorption.
• compositions of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions such as by admixture with a pharmaceutically acceptable carrier vehicle. Suitable vehicles and their formulation are described, for example, in Remington's Pharmaceutical Science (16th Ed.), Osol, A., ed. , Mack, Easton, PA (1980). In order to form a pharmaceutically acceptable composition suitable fo effective administration, such compositions will contain an effective amount of an inhibitor, either alone or in combination, with a suitable carrier vehicle.
• Controlled release preparations may be achieved by the use of polymers to comple or absorb the antibody or antibody fragments/ therapeutic compositions of the present invention.
• the therapeutic or diagnostic compositions of the present invention will be administered to an individual in therapeutically effective amounts. That is in an amount sufficient to prolong the function of a transplanted allograft and prevent transplant rejection. Th effective amount of the composition will vary according to t weight, sex, age, and medical history of the individual. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient condition, the type of allograft, the kinetics of interactio between the target protein and the therapeutic composition, etc. Generally, the composition will be administered in dos ranging from about 1 ⁇ g to about 200 mg antibodies, more generally about 50 ⁇ g to about 100 mg. Animal models may be utilized to further define specific dosages.
• the antibody/inhibitor molecules of the present inventi may be dissolved in any physiologically tolerated liquid in order to prepare an injectable bolus. It is preferable to prepare such a bolus by dissolving the molecule in normal saline.
• compositions of the invention are generally utilized to treat a transplant recipient before and/or following transplantation.
• the treatment may be repeated to maintain the function of a transplanted allograft
• the composition is administered before transplantation or immediately following the transplant operation.
• the duration of treatment may vary from about several hours to several weeks depending upon the patient's condition. Alternatively a series of treatments may be given for the first hours, days or weeks following transplant. Onc the initial treatment or series of treatments is completed, the composition will only be administered occasionally. That is, after the initial treatments, the composition will only b administered upon the development of complications or the indication of transplant rejection.
• adhesion molecules are involved in the inflammatory response, it is recognized that the methods of the present invention can be utilized to treat inflammatory reactions.
• the method can further be utilized to suppress autoimmune diseases, or other T-cell mediated responses.
• T cell immune recognition requires adhesion receptors as well as the T cell receptor by promoting attachment of T cells to their targets and transduce regulatory signals to the T cell.
• Lymphocyte function associated antigen 1 LFA-1
• IAM-1 intercellular adhesion molecule 1
• LFA-1 is required for a broad range of leukocyte functions, including T cell proliferation (Davignon et al. , Proc. Natl. Acad. Sci. USA 7_8_:4535-4539 (1981)) and T-helper and B lymphocyte responses (DeFranco, A.L. , Nature 351:603-604 (1991)).
• T cell proliferation (Davignon et al. , Proc. Natl. Acad. Sci. USA 7_8_:4535-4539 (1981))
• T-helper and B lymphocyte responses DeFranco, A.L. , Nature 351:603-604 (1991)
• Activation of antigen receptors on the T cell Springer, T.A. , Nature 364:425-433 (1990)
• B cell Dan and Rock, J. Immunol. 146.(10) :3273-9 (1991) causes LFA-1 to bind its ligand with higher affinity.
• Balb/c (H2 d ) All animals were purchased from Charles River Resources (Boston) . All animal experiments were approved by the Committee on Research Animal Care Protocol Review Group and carried out according to Massachusetts General Hospital guidelines.
• Hearts were heterotopically transplanted into C3H/He (H21 k ) recipients by a microsurgery technique (Isobe et al., Circulation (1991, in press)). Survival of cardiac graft was assessed by daily palpation and the cessation of graft beat was interpreted as the completion of rejection (Isobe et al. , Circulation (1991, in press)).
• mice without any immunosuppression invariably rejecte allografts within ten days (Table 1) .
• Animals treated with the daily doses of 100 ⁇ g of either YN1/1.7 or KBA showed significant prolongation of allograft survival as evidenced b persistence of graft beat, when compared with control mice; however, all these animals subsequently rejected allografts within 50 days.
• Animals treated with same amount of M18/2 di not show any increase in graft survival.
• mice were challenged with skin grafting.
• cardiac allografts 65 to 72 days
• cardiac allografts 65 to 72 days
• C57BL/6, H2 b third party body skin simultaneously.
• All animals normally rejected thir party skin between 11 and 14 days after transplantation; however, they accepted donor syngeneic skin more than 60 days, or as long as observation was made. All cardiac grafts kept beating during observation. The results clearly indicate antigenspecific tolerance was present in these mice.
• ICAM-1 has another counter-receptor, Mac-1 (Diamond et aL. , Cell 65:961-971 (1991)), which is expressed primarily on myeloid and natural killer cells (Kishimoto et al. , Adv. Immunol. 46:146-182 (1989)).
• Mac-1 Diamond et aL. , Cell 65:961-971 (1991)
• myeloid and natural killer cells Kermoto et al. , Adv. Immunol. 46:146-182 (1989)
• Cytotoxic T lymphocyte assay Recipient C3H/He mice were sacrificed at 7, 40 or 75 days after transplantatio of Balb/c mouse heart. They received 100 ⁇ g of either YN1/1.7, KBA, or 50 ⁇ g each of the two antibodies daily starting the day of transplantation until the 5th day. Fresh spleen cells were washed three times after a lysis of red blood cell by 175 Mm ammonium chloride. Standard 4h cell mediated lympholysis assay was performed using P815 cells labeled with 51 chromium as target cells (4xl ⁇ Vwell) . Result are expressed as percent lysis. Data are average of triplicate and spontaneous re]ease was 15-25% of maximal release in all experiments. The experiment was repeated with consistent results.

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• Health & Medical Sciences (AREA)
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• Organic Chemistry (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• Proteomics, Peptides & Aminoacids (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
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• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

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• 1992
  • 1992-09-29 AU AU27829/92A patent/AU667487B2/en not_active Ceased
  • 1992-09-29 WO PCT/US1992/008279 patent/WO1993006864A1/en not_active Application Discontinuation
  • 1992-09-29 JP JP5507007A patent/JPH07502727A/ja active Pending
  • 1992-09-29 CA CA002120500A patent/CA2120500A1/en not_active Abandoned
  • 1992-09-29 HU HU9400930A patent/HUT69725A/hu unknown
  • 1992-09-29 EP EP92922110A patent/EP0610298A1/en not_active Withdrawn
  • 1992-09-30 ZA ZA927503A patent/ZA927503B/xx unknown
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