| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | March 25, 2003 |
| PATENT TITLE |
Method for inhibiting complement activation |
| PATENT ABSTRACT |
A method of inhibiting complement activation, particularly by a transplanted tissue, in a warm-blooded vertebrate. The method includes administering a therapeutically effective amount of a platelet activity modulator to a warm-blooded vertebrate before, during or after a tissue is transplanted to the warm-blooded vertebrate, whereby complement activation by the transplanted tissue is inhibited. The platelet activity modulator can include a combination of a GPIb modulator and a GPIIb/GPIIIa modulator. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 1, 2001 |
| PATENT REFERENCES CITED |
Ekre, Hans-Peter, "Inhibition of Human and Guinea Pig Complement by Heparin Fractions Differing in Affinity for Antithrombin III or in Average Molecular Weight," International Journal of Immunopharmacology (Elmsford, NY, US), vol. 7 (No. 2),p. 271-275, ( Sep. 21, 1984). Bach, et al., "Delayed xenograft rejection," Immunol. Today, Elsevier Publications (Cambridge, GB), vol. 17 ( No. 8), p. 379-384, ( Aug. 1, 1996). Dorling, et al., "Clinical xenotransplantation of solid organs," The Lancet, p. 867-871, ( Mar. 22, 1997). Hoelschermann, et al., "Evaluation of Recombinant Hirudin in the Prevention of Experimental Cardiac Transplant Vasculopathy," ( Nov. 2, 1999). "The effects of cyclosporin A, ticlopidine hydrochloride and cobra venom factor on the hyperacute rejection of disocrodant renal xenografts", Green et al, 1980, Investigative and Cell Pathology, 3(4), 415-416.* "Platelet Thrombus Formation on injured Endothelial Cell Monolayers", Nollert et al., www.aiche.org, 1999.* "Cardiovascular Pharmacotherapy in Patients following Myocardial Infarction-the Role of Anti-platelet Agents, Anti-coagulants and Angiotensin Converting Enzyme Inhibitors", Yu-An Ding, Chin Med J (Taipei) 1996;57;S232-4.* "Inhibition of von Willebrand Factor Binding to Platelet GP lb by a Fractionated Aurintricarboxylic Acid Prevents Restenosis After Vascular Injury in Hamster Carotid Artery", Matsuno et al., 1997, 96:1299-1304.* Bode et al., "Plasmin Activity and Complement Activation During Storage of Citrated Platelet Concentrates," J. Lab. Clin. Red., vol. 113 (No. 1), p. 94-102, (1989). Bruggemann et al., "Strategies for Expressing Himan Antibody Repertoires in Transgenic Mice," Immunol. Today, vol. 17 (No. 8), p. 391-397, (Aug. 1996). Campbell, "Nuclear Transfer in Farm Animal Species," Semin. Cell. Dev. Biol., vol. 10 (No. 3), p. 245-252, (Jun. 1999). Cibelli et al., "Cloned Transgenic Calves Produced from Nonquiescent Fetal Fibroblasts," Science, vol. 280 (No. 5367), p. 1256-1258, (May 22, 1998). Coller et al., "New Antiplatelet Agents: Platelet GPIIb/IIIa Antagonists," Thrombosis and Haomostasis, vol. 74 (No. 1), p. 302-308, (1995). Girma et al., "Aurin Tricarboxylic Acid Inhibits Platelet Adhesion to Collagen by Binding to the 509-695 Disulphide Loop of von Willebrand Factor and Competing with Glycoprotein Ib," p. 707-713, (1992). Jakobovits, "Production of Fully Human Antibodies by Transgenic Mice," Curr. Opin. Biotechnol., vol. 6 (No. 5), p. 561-566, (Oct. 1995). King et al., "Will Blocking the Plately Save the Diabetic?," Circulation, vol. 100, p. 2466-2468, (1999). Lonberg et al., "Human Antibodies from Transgenic Mice," Imt. Rev. Immunol., vol. 13 (No. 1), p. 65-93, (1995). Neuberger et al., "Monoclonal Antibodies. Mice Perform a Human Repertoire,"Nature, vol. 386 (No. 6620), p. 25-26, (Mar. 6, 1997). Nguyen et al., "Production of Human Monoclonal Antibodies in SCID Mouse," Microbiol. Immunol., vol. 41 (No. 12), p. 901-907, (1997). Nurden et al., "Platelet Glycoprotein IIb/IIIa Inhibitors," Arterioscler. Thromb. Vasc. Biol., p. 2835-2840, (1999). Schnieke et al., "Human Factor IX Transgenic Sheep Produced by Transfer of Nuclei from Transfected Fetal Fibroblasts," Science, vol. 278 (No. 5346), p. 2130-2133, (Dec. 19, 1997). Sims et al., "Regulatory Control of Complement on Blood Platelets," The Journal of Biological Chemistry, vol. 264 (No. 32), p. 19228-19235, (Nov. 15, 1989). Sundsmo et al., "Complement Activation in Type 1 Human Diabetes," Clin. Immunol. Immunopathol., vol. 35 (No. 2), p. 211-225, (May 1985). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method of inhibiting complement activation in a warm-blooded vertebrate in which said inhibition is desired, the method comprising administering a therapeutically effective amount of a platelet activity modulator to a warm-blooded vertebrate, wherein the platelet activity modulator comprises a combination of a first composition comprising a GPIb inhibitor and a second composition comprising a GPIIb/GPIIIa inhibitor, whereby complement activation is inhibited. 2. A method of inhibiting complement activation by a transplanted tissue in a warn-blooded vertebrate, the method comprising administering a therapeutically effective amount of a platelet activity modulator to a warm-blooded vertebrate before, during or after a tissue is transplanted to the warmblooded vertebrate, wherein the platelet activity modulator comprises a combination of a first composition comprising a GPIb inhibitor and a second composition comprising a GPIIb/GPIIIa inhibitor, whereby complement activation by the transplanted tissue is inhibited. 3. The method of claim 1, wherein the GPIb inhibitor comprises aurin tricarboxylic acid. 4. The method of claim 1, wherein the GPIb inhibitor comprises an antibody that blocks GPIb activity. 5. The method of claim 1, wherein the GPIIb/GPIIIa inhibitor comprises SC52012A. 6. The method of claim 1, wherein the GPIIb/GPIIIa inhibitor comprises an antibody that blocks GPIIb/GPIIIa activity. 7. The method of claim 1, wherein the therapeutically effective amount of the platelet activity modulator ranges from about 0.01 mg to about 10,000 mg per day. 8. The method of claim 7, wherein the therapeutically effective amount of the platelet activity modulator ranges from about 0.1 mg to about 1,000 mg per day. 9. The method of claim 8, wherein the therapeutically effective amount of the platelet activity modulator ranges from about 1 mg to about 300 mg per day. 10. The method of claim 2, wherein the GPIb inhibitor comprises aurin tricarboxylic acid. 11. The method of claim 2, wherein the GPIb inhibitor compnses an antibody that blocks GPIb activity. 12. The method of claim 2, wherein the GPIIb/GPIIIa inhibitor comprises SC52012A. 13. The method of claim 2, wherein the GPIIb/GPIIIa inhibitor comprises an antibody that blocks GPIb/GPIIIa activity. 14. The method of claim 2, wherein the therapeutically effective amount of the platelet activity modulator ranges from about 0.01 mg to about 10,000 mg per day. 15. The method of claim 14, wherein the therapeutically effective amount of the platelet activity modulator ranges from about 0.1 mg to abouti 1,000 mg per day. 16. The method of claim 15, wherein the therapeutically effective amount of the platelet activity modulator ranges from about 1 mg to about 300 mg per day. 17. The method of claim 2, wherein the transplanted tissue is a vascularized tissue. 18. The method of claim 17, wherein the vascularized tissue is selected from the group consisting of heart, lung, liver, kidney, pancreas and combinations thereof. 19. The method of claim 2, wherein the transplanted tissue is a xenongrft tissue. 20. The method of claim 19, wherein the xenograft tissue is a vascularized xenograft tissue. 21. The method of claim 20, wherein the vascularized xenograft tissue is selected from the group consisting of heart, lung, liver, kidney, pancreas and combinations thereof. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
TECHNICAL FIELD The present invention pertains generally to modulation of activation of the complement system. More particularly, the present invention pertains to the inhibition of complement activation through the inhibition of platelet receptors for thrombin/fibrinogen. In a preferred embodiment, the present invention pertains to a method of inhibiting of transplant rejection by blocking complement activation in a recipient. Table of Abbreviations ATA aurintricarboxylic acid C complement, usually followed by a number from 1 to 9 when referencing the factors of the complement system in the immune system C3a complement activation factor C5b-9 complement activation factors CDR complementarity determining region CVF cobra venom factor Fg fibrinogen Fn fibronectin GPlb platelet receptor involved in platelet activation and aggregation GPllb/llla platelet receptor involved in platelet activation and aggregation HAR hyperacute rejection HCl hydrochloric acid PPP platelet poor plasma PRP platelet rich plasma PVR pulmonary vascular resistance SC52012A selective potent GPllb/llla antagonist TFA trifluoroacetic acid TXA2 thromboxane vWF von Willebrand's Factor BACKGROUND ART The complement system is a complex interaction of plasma proteins and membrane cofactors which act in a multi-step, multi-protein cascade sequence in conjunction with other immunological systems of the body to provide immunity from intrusion of foreign cells. Complement proteins represent up to about 10% of globulins in normal serum of man and other vertebrate's. The term "complement" refers to the non-specific defense system that is activated by the bonding of antibodies to antigens and by this event is directed against specific invaders that have been identified by antibodies. Organ procurement currently poses one of the major problems in organ transplantation, as the number of patients requiring transplants far exceeds the number of organs available. Moreover, a transplanted organ is often rejected by the recipient's body. Thus, even when an organ is available, transplant rejection presents a continuing problem. Xenotransplantation may provide a solution to the shortage of organs for transplant. Phylogenetically, non-human primates are the most closely related species to humans and might therefore represent the first choice as donors. In 1969, Reetsma et al. achieved the first successful kidney human xenograft from a chimpanzee (Reetsma, K., et al., 1964, Ann. Surg. 160:384). However, the potential utilization of primate donors is limited by insufficient numbers, legal and ethical considerations, and the potential for transmitting dangerous viral diseases. Swine represent one of the few large animal species in which breeding characteristics make genetic experiments possible, making it possible to develop MHC homozygous lines of miniature swine, for example. Miniature swine can be maintained at maximum adult weights of 200 to 300 lbs and are anatomically and physiologically close to humans. Therefore, the organs of miniature swine seem appropriate for use as xenografts for human beings of all ages. However, problems associated with transplant rejection also persist with respect to xenograft organs from swine and from other donors. Therefore, there remains a continuing and long-felt need for therapeutic methods that inhibit transplant rejection and that faciliate the use of xenograftt organs in transplant procedures. SUMMARY OF THE INVENTION A method of modulating complement activation in a warm-blooded vertebrate is disclosed. The method comprises administering a therapeutically effective amount of a platelet activity modulator to a warm-blooded vertebrate, whereby complement activation is modulated. The platelet activity modulator preferably comprises a combination of a GPIb modulator and a GPIIb/GPIIIa modulator. A method of inhibiting complement activation by a transplanted tissue in a warm-blooded vertebrate is also disclosed. The method comprises administering a therapeutically effective amount of a platelet activity modulator to a warm-blooded vertebrate before, during or after a tissue is transplanted to the warm-blooded vertebrate, whereby complement activation, by the transplanted tissue is inhibited. The platelet activity modulator preferably comprises a combination of a GPIb modulator and a GPIIb/GPIIIa modulator. The therapeutically effective amount of the platelet activity modulator ranges from about 0.01 mg to about 10,000 mg per day, preferably from about 0.1 mg to about 1,000 mg per day, and more preferably from about 1 mg to about 300 mg per day. The transplanted tissue can be a vascularized tissue. The vascularized tissue can include, but is not limited to heart, lung, liver, kidney, pancreas and combinations thereof. The transplanted tissue can be xenograft tissue. The xenograft tissue can be vascularized xenograft tissue. The vascularized xenograft tissue can include, but is not limited to, heart, lung, liver, kidney, pancreas and combinations thereof. Optionally, the xenograft tissue is obtained from a donor animal having a deficient platelet activity pathway. A method of inhibiting rejection of a transplanted tissue in a warm-blooded vertebrate is also disclosed. The method comprises administering a therapeutically effective amount of a GPIb modulator and a GPIIb/GPIIIa modulator to a warm-blooded vertebrate before, during or after a tissue is transplanted to the warm-blooded vertebrate, whereby rejection of the transplanted tissue is inhibited. A method of enhancing tolerance of a xenograft transplant in a recipient is also disclosed. The method comprises administering a therapeutically effective amount of a GPIb modulator and a GPIIb/GPIIIa modulator to a recipient before, during or after the recipient receives a xenograft transplant, whereby tolerance of the xenograft transplant is enhanced. Accordingly, it is an object of the present invention to provide a novel method for inhibiting transplant rejection. This and other objects are achieved in whole or in part by the present invention. An object of the invention having been stated hereinabove, other objects will become evident as the description proceeds when taken in connection with the accompanying Drawings and Laboratory Examples as best described hereinbelow. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A and 1B are graphs of the change (delta) in C3a plasma levels (ng/ml) versus time in minutes for the experiment described in Example 6 (.circle-solid.=untreated; .smallcircle.=ATA+SC; .tangle-soliddn.=GPIb+GPIIbIIIa monoclonal antibody). |
| PATENT PHOTOCOPY | available on request |
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