Growth factor antagonists for organ transplant alloimmunity and arteriosclerosis

Abstract

The present invention provides materials and methods for antagonizing the function of vascular endothelial growth factor receptors, platelet derived growth factor receptors and other receptors, to prevent, inhibit, or ameliorate allograft rejection or arteriosclerosis in organisms that receive an organ transplant.

1 . (canceled) 
     
     
         2 . A method for inhibiting rejection of a vascularized tissue or vascularized organ transplant, or for inhibiting arteriosclerosis in a human allograft transplant recipient, comprising:
 administering to a human allograft transplant recipient a composition that comprises a nucleic acid that comprises a nucleotide sequence that encodes an endothelial growth factor inhibitor, wherein the nucleic acid is expressible in cells of the human allograft transplant recipient or expressible in cells of the transplanted tissue or organ to produce an amount of the endothelial growth factor inhibitor effective to inhibit rejection or inhibit arteriosclerosis,   wherein the endothelial growth factor inhibitor comprises a soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C or inhibits stimulation of human VEGFR-3 by VEGF-D.   
     
     
         3 . The method of  claim 2 , wherein the nucleic acid further comprises at least one expression control sequence operatively connected to the sequence that encodes the endothelial growth factor inhibitor. 
     
     
         4 . The method of  claim 3 , comprising administering an expression vector that comprises the nucleic acid and the at least one expression control sequence. 
     
     
         5 . The method of  claim 4 , wherein the vector comprises a replication-deficient viral vector. 
     
     
         6 . The method of  claim 5 , wherein the vector comprises at least one member selected from the group consisting of a retrovirus, an adenovirus, an adeno-associated virus. a vaccinia virus, and a herpesvirus. 
     
     
         7 . The method of  claim 4 , wherein expression of the vector is inducible by administration of an exogenous pharmaceutical agent. 
     
     
         8 . The method of  claim 4 , wherein expression of the vector is induced by an endogenous stress in the organ transplant recipient. 
     
     
         9 . The method of  claim 8 , wherein the stress comprises an elevation of a biological marker correlated with rejection. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . The method of  claim 4 , wherein the composition further comprises a pharmaceutically acceptable carrier, and
 wherein the composition is administered intravenously, intramuscularly, intraperitoneally, or perorally.   
     
     
         14 . The method of  claim 4 , where the transplant is a vascularized tissue transplant. 
     
     
         15 - 16 . (canceled) 
     
     
         17 . The method of  claim 4 , wherein the transplant comprises a vascularized organ, or comprises an organ fragment capable of performing functions of the organ or capable of regenerating into the organ. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 4 , wherein the transplant comprises an organ selected from the group consisting of a heart, a lung, a liver, and a kidney. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 4 , wherein the composition is administered locally to the transplanted, vascularized tissue or vascularized organ in the human allograft transplant recipient. 
     
     
         22 . The method of  claim 4 , wherein the composition is administered systemically to the human allograft transplant recipient. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . The method of  claim 4 , further comprising administering the composition to the organ or the organ donor before the transplant. 
     
     
         26 . The method of  claim 4 , further comprising repeated administration of the composition to the human allograft transplant recipient. 
     
     
         27 . The method of  claim 4 , wherein the composition is administered to the human allograft transplant recipient perioperatively, relative to the transplant operation. 
     
     
         28 . The method of  claim 4 , wherein the composition is administered to the human allograft transplant recipient for 1-90 days post-operatively, relative to the transplant operation. 
     
     
         29 . The method of  claim 4 , wherein the composition is administered to the human allograft transplant recipient for 1-60 days post-operatively, relative to the transplant operation. 
     
     
         30 . The method of  claim 4 , wherein the composition is administered to the human allograft transplant recipient for 1-30 days post-operatively, relative to the transplant operation. 
     
     
         31 . The method of  claim 4 , wherein the composition is administered to the human allograft transplant recipient for 1-15 days post-operatively, relative to the transplant operation. 
     
     
         32 . The method of  claim 4 , comprising:
 screening the human allograft transplant recipient for symptoms of an acute rejection reaction; and   administering the composition to the human allograft transplant recipient upon detection of symptoms of acute rejection, in an amount effective to inhibit the rejection.   
     
     
         33 - 38 . (canceled) 
     
     
         39 . The method of  claim 4 , wherein the encoded polypeptide comprises a soluble human VEGFR-3 extracellular domain polypeptide that binds VEGF-C or VEGF-D. 
     
     
         40 . The method of  claim 39 , wherein the encoded soluble VEGFR-3 polypeptide comprises the VEGFR-3 extracellular domain, or a fragment thereof sufficient to bind VEGF-C or VEGF-D, and wherein the fragment includes amino acids 138-226 of SEQ ID NO: 6. 
     
     
         41 . The method of  claim 39 , wherein the encoded soluble VEGFR-3 polypeptide comprises the first and second immunoglobulin-like domains of the VEGFR-3. 
     
     
         42 . The method of  claim 39 , wherein the encoded soluble VEGFR-3 polypeptide comprises the first, second, and third immunoglobulin-like domains of the VEGFR-3. 
     
     
         43 . The method of  claim 39 , wherein the encoded soluble VEGFR-3 polypeptide is fused to an immunoglobulin constant domain. 
     
     
         44 - 50 . (canceled) 
     
     
         51 . The method of  claim 4 , further comprising administering to the human allograft transplant recipient a composition that comprises at least one growth factor inhibitor selected from the group consisting of:
 inhibitors of VEGFR 1;   inhibitors of VEGFR 2;   inhibitors of PDGFR-alpha; and   inhibitors of PDGFR-beta;   wherein the combination of inhibitors are administered in amounts effective to inhibit rejection or inhibit arteriosclerosis.   
     
     
         52 - 57 . (canceled) 
     
     
         58 . The method of  claim 4 , further comprising administering an immunosuppressive agent to the human allograft transplant recipient, wherein the immunosuppressive agent comprises at least one compound selected from the group consisting of: Tacrolimus, Mycophenolic acid, Prednisone, cyclosporine, Azathioprine, Basiliximab, Daclizumab, Muromonab-CD3, Mycophenolate Mofetil, Sirolimus, Methylprednisolone, Thymoglobulin, Rapamycin, and Interleukin-2 Receptor Antagonist. 
     
     
         59 . The method of  claim 4 , further comprising administering an antibiotic or antifungal agent to the human allograft transplant recipient. 
     
     
         60 . The method of  claim 4 , further comprising administering to a human donor organism a composition that comprises an endothelial growth factor inhibitor, prior to harvesting a vascularized tissue or vascularized organ for transplantation into the human allograft transplant recipient. 
     
     
         61 . The method of  claim 4 , further comprising contacting a vascularized tissue or vascularized organ with a composition that comprises an endothelial growth factor inhibitor, prior to transplanting the vascularized tissue or vascularized organ into the human allograft transplant recipient. 
     
     
         62 . The method of  claim 4 , further comprising administering to a human donor, prior to harvesting a vascularized tissue or vascularized organ for transplantation, a composition that comprises a nucleic acid that comprises a nucleotide sequence that encodes an endothelial growth factor inhibitor, wherein the nucleic acid is expressible in cells of the vascularized tissue or vascularized organ to be transplanted. 
     
     
         63 . The method of  claim 4 , further comprising contacting a vascularized tissue or vascularized organ with a composition that comprises a nucleic acid that comprises a nucleotide sequence that encodes an endothelial growth factor inhibitor, prior to transplanting the vascularized tissue or vascularized organ into the recipient. 
     
     
         64 - 67 . (canceled) 
     
     
         68 . The method of  claim 58 , further comprising administering an antibiotic or antifungal agent to the human allograft transplant recipient. 
     
     
         69 . The method of  claim 58 , further comprising administering to a human donor organism a composition that comprises an endothelial growth factor inhibitor, prior to harvesting a vascularized tissue or vascularized organ for transplantation into the human allograft transplant recipient. 
     
     
         70 . The method of  claim 4 , wherein the composition is administered to the human allograft transplant recipient post-operatively, relative to the transplant operation. 
     
     
         71 . A method for inhibiting rejection of a vascularized tissue or vascularized organ transplant, or for inhibiting arteriosclerosis in a human allograft transplant recipient, the method comprising:
 administering to a human allograft transplant recipient a composition that comprises a nucleic acid that comprises a nucleotide sequence that encodes an endothelial growth factor inhibitor, wherein the nucleic acid is expressible in cells of the human allograft transplant recipient or expressible in cells of the transplanted tissue or organ to produce an amount of the endothelial growth factor inhibitor effective to inhibit rejection or inhibit arteriosclerosis,   wherein the endothelial growth factor inhibitor comprises an amino acid sequence at least 95% identical to amino acids 138-226 of SEQ ID NO: 6, that binds VEGF-C or VEGF-D and that inhibits stimulation of human VEGFR-3 by the VEGF-C or the VEGF-D.   
     
     
         72 . The method of  claim 71 , wherein the nucleic acid comprises a nucleotide sequence that encodes an amino acid sequence at least 95% identical to amino acids 47-224 of SEQ ID NO: 6. 
     
     
         73 . The method of  claim 71 , wherein the nucleic acid comprises a nucleotide sequence that encodes an amino acid sequence at least 95% identical to amino acids 47-314 of SEQ ID NO: 6. 
     
     
         74 . The method of  claim 71 , wherein the nucleic acid comprises a nucleotide sequence that encodes an amino acid sequence at least 95% identical to amino acids 24-775 of SEQ ID NO: 6 or fragments thereof that bind VEGF-C. 
     
     
         75 . The method of  claim 73 , wherein the nucleic acid further comprises at least one expression control sequence operatively connected to the sequence that encodes the endothelial growth factor inhibitor. 
     
     
         76 . The method of  claim 75 , comprising administering an expression vector that comprises the nucleic acid and the at least one expression control sequence. 
     
     
         77 . The method of  claim 76 , wherein the vector comprises a replication-deficient viral vector. 
     
     
         78 . The method of  claim 77 , wherein the vector comprises at least one member selected from the group consisting of a retrovirus, an adenovirus, an adeno-associated virus. a vaccinia virus, and a herpesvirus. 
     
     
         79 . The method of  claim 73 , wherein the composition is administered to the recipient for 1-90 days post-operatively, relative to the transplant operation. 
     
     
         80 . The method of  claim 73 , wherein the composition is administered to the recipient for 1-60 days post-operatively, relative to the transplant operation. 
     
     
         81 . The method of  claim 73 , wherein the composition is administered to the recipient for 1-30 days post-operatively, relative to the transplant operation. 
     
     
         82 . The method of  claim 73 , wherein the composition is administered to the recipient for 1-15 days post-operatively, relative to the transplant operation. 
     
     
         83 . The method of  claim 73 , further comprising administering to the recipient a composition that comprises at least one growth factor inhibitor selected from the group consisting of:
 inhibitors of VEGFR-1;   inhibitors of VEGFR-2;   inhibitors of PDGFR-alpha; and   inhibitors of PDGFR-beta;   wherein the combination of inhibitors are administered in amounts effective to inhibit rejection, or inhibit arteriosclerosis.   
     
     
         84 . A method for inhibiting rejection of a transplanted organ, or fragment thereof, the organ selected from the group consisting of a heart, a kidney, a lung, a liver, an intestine, a pancreas, skin, and bone, the method comprising:
 administering to a human transplant recipient a composition that comprises a nucleic acid that comprises a nucleotide sequence that encodes a soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C or inhibits stimulation of human VEGFR-3 by VEGF-D.   
     
     
         85 . The method of  claim 84 , wherein the nucleic acid further comprises at least one expression control sequence operatively connected to the sequence that encodes the endothelial growth factor inhibitor. 
     
     
         86 . The method of  claim 85 , comprising administering an expression vector that comprises the nucleic acid and the at least one expression control sequence. 
     
     
         87 . The method of  claim 86 , wherein the vector comprises a replication-deficient viral vector. 
     
     
         88 . The method of  claim 87 , wherein the vector comprises at least one member selected from the group consisting of a retrovirus, an adenovirus, an adeno-associated virus. a vaccinia virus, and a herpesvirus. 
     
     
         89 . The method of  claim 86 , wherein the composition is administered to the recipient for 1-90 days post-operatively, relative to the transplant operation.