Organ Transplant Solutions and Methods for Transplanting Organs

Abstract

A preservation solution for organs waiting to be transplanted is disclosed; the method of using the solution in a transplantation procedure is also disclosed. The preservation solutions comprise a balanced isotonic aqueous solution comprising sodium, potassium, calcium, magnesium and bicarbonate ions in a physiologically acceptable amount, together with an effective amount of a mutein of the C5a anaphylatoxin which is a C5a receptor antagonist wherein the amino acid residue naturally occurring at sequence position 69 is mutated.

What is claimed is: 
     
         1 .- 20 . (canceled) 
     
     
         21 . A method of preservation, storage and reperfusion of an organ intended for implantation, said method comprising perfusing said organ with a solution comprising:
 (a) a balanced isotonic solution comprising sodium, potassium, calcium, magnesium and bicarbonate ions in a physiologically acceptable amount;   (b) a safe and effective amount of a mutein of the C5a anaphylatoxin which is a C5a receptor antagonist wherein the amino acid residue naturally occurring at sequence position 69 is mutated; and   (c) water.   
     
     
         22 . The method of preservation according to  claim 21  wherein the C5a mutein is present at from about 0.1 to about 10 μM/liter of the solution. 
     
     
         23 . The method of preservation according to  claim 22  wherein the C5a mutein has an amino acid sequence selected from 
       SEQ ID NO: 14 (C5a-(1-66, Cys27Ala-)A8B); 
       SEQ ID NO: 15 (C5a-(1-66, Cys27Ala)-A8B-Leu 70); 
       SEQ ID NO: 16 (C5a-(1-66, Cys27Ala)-Ab8-Cys71); 
       SEQ ID NO: 17 (C5a-(1-66, Cys27Ala)-A8B-Cys73); 
       SEQ ID NO: 18 (C5a-(1-66, Cys27Ala)-A8B-Leu70-Tyr73); 
       SEQ ID NO: 19 (C5a-(1-66, Cys27Ala)-A8B-Lys69-Ala70); 
       SEQ ID NO: 20 (C5a-(1-66, Cys27Arg)-A8B); 
       SEQ ID NO: 21 (C5a-(1-66, Cys27Ala)-A8B-Del.71-73); 
       SEQ ID NO: 22 (C5a-(1-66, Cys-3, Gly-2, -1,Cys27Ala)-A8B); and 
       SEQ ID NO: 39 (C5a-(1-66, Cys27Ala)A5a). 
     
     
         24 . A method of preservation of organs intended for implantation, said method comprising perfusing the body of the dead organ donor, prior to removal of the organs, with a solution comprising:
 (a) a balanced isotonic solution comprising sodium, potassium, calcium, magnesium and bicarbonate ions in a physiologically acceptable amount;   (b) a safe and effective amount of a mutein of the C5a anaphylatoxin which is a C5a receptor antagonist wherein the amino acid residue naturally occurring at sequence position 69 is mutated; and   (c) water.   
     
     
         25 . The method of preservation according to  claim 24  wherein the C5a mutein has an amino acid sequence selected from 
       SEQ ID NO: 14 (C5a-(1-66, Cys27Ala-)A8B); 
       SEQ ID NO: 15 (C5a-(1-66, Cys27Ala)-A8B-Leu 70); 
       SEQ ID NO: 16 (C5a-(1-66, Cys27Ala)-Ab8-Cys71); 
       SEQ ID NO: 17 (C5a-(1-66, Cys27Ala)-A8B-Cys73); 
       SEQ ID NO: 18 (C5a-(1-66, Cys27Ala)-A8B-Leu70-Tyr73); 
       SEQ ID NO: 19 (C5a-(1-66, Cys27Ala)-A8B-Lys69-Ala70); 
       SEQ ID NO: 20 (C5a-(1-66, Cys27Arg)-A8B); 
       SEQ ID NO: 21 (C5a-(1-66, Cys27Ala)-A8B-Del.71-73); 
       SEQ ID NO: 22 (C5a-(1-66, Cys-3, Gly-2, -1,Cys27Ala)-A8B); and 
       SEQ ID NO: 39 (C5a-(1-66, Cys27Ala)A5a). 
     
     
         26 . The method of preservation according to  claim 25  wherein the C5a mutein is present at from about 0.1 to about 10 μM/liter of the solution. 
     
     
         27 . The method of  claim 21 , wherein, in the mutein, the amino acid residue at sequence position 69 is replaced by leucine or a positively charged amino acid residue. 
     
     
         28 . The method of  claim 21 , wherein, in the mutein, the amino acid residue at sequence position 67 is mutated. 
     
     
         29 . The method of  claim 21 , wherein, in the mutein, at least one of the amino acid residues at sequence positions 70 to 74 of the natural amino sequence is mutated or at least one of the amino acid residues at said sequence positions 70 to 74 is deleted. 
     
     
         30 . The method of  claim 21 , wherein, in the mutein, the positively charged amino acid residue at sequence position 69 is Arg or Lys. 
     
     
         31 . The method of  claim 21 , wherein the mutein comprises at sequence position 67 an aromatic amino acid selected from the group consisting of Phe, Trp and Tyr. 
     
     
         32 . The method of  claim 21 , wherein the mutein comprises a hydrophobic amino acid residue at sequence position 70. 
     
     
         33 . The method of  claim 21 , wherein the mutein comprises Leu or Ala at sequence position 70. 
     
     
         34 . The method of  claim 21 , wherein the mutein comprises Ser at sequence position 70. 
     
     
         35 . The method of claim  1 , wherein the mutein comprises a terminal sequence selected from the group consisting of SEQ ID NO: 1; SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. 
     
     
         36 . The method of  claim 21 , wherein the mutein further comprises Arg at sequence position 27. 
     
     
         37 . The method of  claim 21 , wherein the mutein has an amino acid sequence selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 10 SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14; SEQ ID NO: 15; SEQ ID NO: 16; SEQ ID NO: 17; SEQ ID NO: 18. 
     
     
         38 . The method of  claim 21 , wherein the mutein is fused to a protein or a peptide tag with the proviso that the fusion proteins of the mutein A8B with Jun/Fos alone or with Jun/Fos and the minor coat protein (pIII) of the filamentous M13 phage mutein A8B, wherein the Jun/Fos moiety is fused to the N-terminus of the mutein A8B, as well as the mutein A8B having a hexahistidine tag directly fused to the N-terminus are excluded. 
     
     
         39 . The method of  claim 21 , wherein the mutein is conjugated to a protein moiety via a suitable peptidic or non-peptidic linker which enhances the in vivo half-life of the mutein.