Patent EA-002549-B1 (EA)
Title: Use of a cd40:cd154 binding interruptor to prevent counter adaptive immune responses, particularly graft rejection
Inventor: KIRK ALLAN D
IPC: A61K38/13
Filed: 1998-05-15
Abstract: 1. A method of inhibiting rejection of a tissue graft by a primate graft recipient, comprising the step of administering an effective amount of a CD40:CD154 binding interruptor to the graft recipient, wherein said CD40:CD154 binding interruptor is a blocking agent specifically bound with CD154, its antigen-binding fragment or a derivative thereof. 2. A method according to claim 1, wherein the anti-CD40L compound is a monoclonal antibody. 3. A method according to claim 2, wherein the monoclonal antibody binds to the 5c8 antigen. 4. A method according to claim 3, wherein the monoclonal antibody has the antigen-specific binding characteristics of the 5c8 antibody produced by ATCC Accession No. HB 10916. 5. A method of reversing acute rejection of grafted tissue in a primate graft recipient, comprising the step of administering an effective amount of a CD40:CD154 binding interruptor to the graft recipient, wherein said CD40:CD154 binding interruptor is a blocking agent specifically bound with CD154, its antigen-binding fragment or a derivative thereof. 6. A method according to claim 5, wherein the grafted tissue is selected from renal, hepatic, cardiac, pancreatic, skin, vascular, nerve, bone and cartilage tissue. 7. A method of prolonging survival of grafted tissue in a primate graft recipient, comprising the step of administering an effective amount of a CD40:CD154 binding interruptor to the graft recipient, wherein said CD40:CD154 binding interruptor is a blocking agent specifically bound with CD154, its antigen-binding fragment or a derivative thereof. 8. A method of attenuating immunological complications of failure of grafted tissue in a primate graft recipient, comprising the step of administering an effective amount of a CD40:CD154 binding interruptor to the graft recipient, wherein said CD40:CD154 binding interruptor is a blocking agent specifically bound with CD154, its antigen-binding fragment or a derivative thereof. 9. A method according to claim 1, 6, 7 or 8, wherein the grafted tissue is allogeneic to said primate. 10. A method according to claim 1, 6, 7 or 8, wherein the grafted tissue is xenogeneic to said primate. 11. A method according to claim 1, 6, 7 or 8, wherein the grafted tissue comprises isolated or suspended cells. 12. A method according to claim 11, wherein said comprises isolated or suspended cells are selected from the group consisting of: a) peripheral blood cells; and b) bone marrow cells or any hematopoeitic component thereof. 13. A composition comprising a CD40:CD154 (CD40L) binding interruptor, its antigen-binding fragment or a derivative thereof; and, an immunosuppressive or immunomodulatory compound. 14. A composition according to claim 13, wherein the immunosuppressive or immunomodulatory compound is selected from the group consistong of (a) an agent that interrupts T cell costimulatory signalling via CD28; (b) an agent that interrupts calcineurin signalling; (c) a corticosteroid or an antiproliferative agent; or (d) tacrolimus, sirolimus, mycophenolate mofetil, mizorubine, deoxyspergualin, brequinar sodium, leflunomide, and azaspirane. 15. A composition according to claim 14, wherein said anti-CD40L compound is a monoclonal antibody. 16. A method according to claim 15, wherein the monoclonal antibody binds to the 5c8 antigen. 17. A method of inhibiting rejection of a tissue graft by a primate graft recipient, comprising the steps of administering an effective amount of anyone of said compositions according to claims 13-16. 18. A method of reversing acute rejection of grafted tissue in a graft recipient, comprising the step of administering an effective amount of anyone of said compositions according to claims 13-16. 19. A method of prolonging survival of grafted tissue in a primate graft recipient, comprising the step of administering an effective amount of anyone of said compositions according to claims 13-16. 20. A method of attenuating immunological complications of failure of grafted tissue in a primate graft recipient, comprising the step of administering an effective amount of anyone of said compositions according to claims 13-16. 21. A method according to any of claims 17-20, wherein the immunosuppressive or immunomodulatory compound is an agent that interrupts T cell costimulatory signalling via CD28. 22. A method according to any of claims 17-20, wherein the immunosuppressive or immunomodulatory compound is an agent that interrupts calcineurin signalling. 23. A method according to claim 22, wherein the agent is selected from cyclosporine and tacrolimus. 24. A method according to any of claims 17-20, wherein the immunosuppressive or immunomodulatory compound is a corticosteroid or an antiproliferative agent. 25. A method according to any of claims 17-20, wherein the immunosuppressive or immunomodulatory compound is selected from tacrolimus, sirolimus, mycophenolate mofetil, mizorubine, deoxyspergualin, brequinar sodium, leflunomide, and azaspirane. 26. A method of inhibiting rejection of a tissue graft by a primate graft recipient, comprising the steps of implanting a tissue graft into said primate; and, administering an effective amount of a CD40:CD154 binding interruptor to the graft recipient on days 2, 4, 6, 8, 12, 16, and 28, counted from the day of implantation, wherein said CD40:CD154 binding interruptor is a blocking agent specifically bound with CD154, its antigen-binding fragment or a derivative thereof. 27. A method of inhibiting rejection of a tissue graft by a primate graft recipient, comprising the steps of: administering an effective amount of a CD40:CD154 binding interruptor to a prospective primate graft recipient; one day thereafter, implanting a tissue graft into said primate and concomitantly administering an effective amount of the CD40:CD154 binding interruptor to said primate; and, administering effective amounts of the CD40:CD154 binding interruptor to the recipient on days 3, 10, 18, and 28, counted from the day of implantation, wherein said CD40:CD154 binding interruptor is a blocking agent specifically bound with CD154, its antigen-binding fragment or a derivative thereof. 28. A method according to claim 27, comprising the additional step of repeating administration of an effective amount of the CD40:CD154 binding interruptor to said primate on a monthly basis, beginning one month after day 28, as counted from the day of inplantation. 29. A method of reversing acute rejection of grafted tissue in a primate graft recipient, comprising the step of administering an effective amount of a CD40:CD154 binding interruptor to said primate graft recipient on the day on which the recipient presents indicia of acute graft rejection, and on days 3, 10, 18, and 28 thereafter, wherein said CD40:CD154 binding interruptor is a blocking agent specifically bound with CD154, its antigen-binding fragment or a derivative thereof. 30. A method according to claim 29, comprising the additional step of repeating administration of an effective amount of the CD40:CD154 binding interruptor to said primate on a monthly basis, beginning one month after day 28, as counted from the day of presentation with indicia of acute graft rejection. 31. A method according to any of claims 1, 5, 7, 8, 26, 27 or 29, wherein said primate is human. 32. A method according to any of claims 1, 5, 7, 8, 26, 27 or 29, wherein said CD40:CD154 binding interruptor is administered to said primate via a manner selected from the group consisting of: (a) parenteral route; (b) biocompatible or bioerodable sustained release implant; (c) implantation of an infusion pump; (d) an oral or enteral administration; and (e) topical administration. 33. A method according to any of claims 1, 5, 7, 8, 26, 27 or 29, wherein said CD40:CD154 binding interruptor is administered to a donor or graft tissue prior to integration of said tissue into said primate graft recipient.