Compositions and methods for treating hematological cancers targeting the sirpalpha cd47 interaction

Abstract

The invention relates to modulating the SIRPα-CD47 interaction in order to treat hematological cancer and compounds therefor. In some embodiments, there is provided methods and uses of SIRPα polypeptides, fragments and fusion proteins for treating hematological cancer, preferably human acute myeloid leukemia.

1 . A method for treating a human subject with a hematological cancer comprising administering to the subject a therapeutically effective amount of a polypeptide capable of binding to the extracellular domain of human CD47 and modulating the interaction between human Sirpα and human CD47, wherein the polypeptide comprises soluble human Sirpα, or a CD47-binding extracellular domain fragment thereof. 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the polypeptide is fused to a second protein comprising an Fc portion of IgG to form a fusion protein. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 5 , wherein the resulting fusion protein comprises SEQ ID NO: 13. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the hematological cancer is leukemia. 
     
     
         10 . The method of  claim 9 , wherein the leukemia is selected from acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, myeloproliferative disorder/neoplasm and myelodysplastic syndrome. 
     
     
         11 . The method of  claim 10 , wherein the leukemia is human acute myeloid leukemia. 
     
     
         12 . The method of  claim 1 , wherein the hematological cancer is a lymphoma or myeloma selected from Hodgkin's lymphoma, both indolent and aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, follicular lymphoma (small cell and large cell), multiple myeloma (MM), giant cell myeloma, heavy-chain myeloma, and light chain or Bence-Jones myeloma. 
     
     
         13 - 26 . (canceled) 
     
     
         27 . A method of prognosing likelihood of survival of a patient with a hematological cancer comprising:
 a) sequencing the Sirpα gene from the patient; and   b) determining whether a polymorphism that results in an amino acid difference exists in the Sirpα gene from the patient, wherein the amino acid difference is at least one of:
 (i) replacement of at least one of residues at positions 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 2 with corresponding residues 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 1; or 
 (ii) deletion of at least one of residues 129 and 130 of SEQ ID NO: 2. 
   
     
     
         28 - 29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the polypeptide is selected from the group consisting of:
 a) a polypeptide consisting of the amino acid sequence of SEQ ID NO: 1;   b) a polypeptide consisting of a CD47-binding fragment of the amino acid sequence of SEQ ID NO: 1, wherein the fragment comprises at least one of residues 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 1; and   c) a CD47-binding variant of one of the polypeptide in a) and b) with up to 1 amino acid insertion, deletion or substitution for every 7 amino acids in length of the polypeptide, wherein the polypeptide comprises at least one of residues 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 1.   
     
     
         31 . The method of  claim 1 , wherein the polypeptide is selected from the group consisting of:
 a) a polypeptide consisting of the amino acid sequence of SEQ ID NO: 2;   b) a polypeptide consisting of a CD47-binding fragment of the amino acid sequence of SEQ ID NO: 2; and   c) a CD47-binding variant of one of the polypeptide in a) and b) with up to 1 amino acid insertion, deletion or substitution for every 7 amino acids in length of the polypeptide; wherein:
 i. at least one of residues at positions 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 2 in the polypeptide is replaced with corresponding residues 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 1; or 
 ii. at least one of residues 129 and 130 of SEQ ID NO: 2 in the polypeptide is deleted. 
   
     
     
         32 . The method of  claim 1 , wherein the polypeptide is selected from the group consisting of:
 a) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-7;   b) a polypeptide consisting of a CD47-binding fragment of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-7; and   c) a CD47-binding variant of one of the polypeptide in a) and b) with up to 1 amino acid insertion, deletion or substitution for every 7 amino acids in length of the polypeptide.   
     
     
         33 . The method of  claim 30 , wherein the polypeptide is the CD47-binding fragment and comprises at least 3 consecutive amino acids in at least one of a region between residues 50-57, 63-71, 74-80, 88-92, 95-100, 103-109, 114-125 or 128-141, inclusive of SEQ ID NO: 1. 
     
     
         34 . The method of  claim 31 , wherein the polypeptide is the CD47-binding fragment and comprises at least 3 consecutive amino acids in at least one of a region between residues 50-57, 63-71, 74-80, 88-92, 95-100, 103-109, 114-125 or 128-143, inclusive of SEQ ID NO: 2. 
     
     
         35 . The method of  claim 32 , wherein the polypeptide is the CD47-binding fragment and comprises at least 3 consecutive amino acids in at least one of a region between residues 24-31, 37-45, 48-54, 62-66, 69-74, 77-83, 88-99 or 102-116, inclusive, of any one of SEQ ID NOs: 4, 6 and 7; or between residues 24-31, 37-45, 48-54, 6266, 69-74, 77-83, 88-99 or 102-115, inclusive, of SEQ ID NO: 5. 
     
     
         36 . The method of  claim 30 , wherein the amino acid insertion, deletion or substitution is a conservative amino acid substitution. 
     
     
         37 . The method of  claim 30 , having no amino acid insertion, deletion or substitution. 
     
     
         38 . (canceled) 
     
     
         39 . The method of  claim 30 , wherein the polypeptide is a CD47-binding fragment and is between 6 and 30 amino acids in length. 
     
     
         40 - 50 . (canceled) 
     
     
         51 . A pharmaceutical composition for treating a hematological cancer, comprising an effective amount of a polypeptide and a pharmaceutically acceptable carrier, the polypeptide selected from the group consisting of:
 a) a polypeptide consisting of the amino acid sequence of SEQ ID NO: 1;   b) a polypeptide consisting of a CD47-binding fragment of the amino acid sequence of SEQ ID NO: 1, wherein the fragment comprises at least one of residues 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 1;   c) a CD47-binding variant of one of the polypeptide in a) and b) with up to 1 amino acid insertion, deletion or substitution for every 7 amino acids in length of the polypeptide, wherein the polypeptide comprises at least one of residues 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 1;   d) a polypeptide consisting of the amino acid sequence of SEQ ID NO: 2;   e) a polypeptide consisting of a CD47-binding fragment of the amino acid sequence of SEQ ID NO: 2;   f) a CD47-binding variant of one of the polypeptide in d) and e) with up to 1 amino acid insertion, deletion or substitution for every 7 amino acids in length of the polypeptide; wherein:
 (i) at least one of residues at positions 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 2 in the polypeptide is replaced with corresponding residues 31, 32, 34, 37, 74, 77, 83, 84, 86, 87, 90, 91, 96, 100, 102, 114, 118, 126 of SEQ ID NO: 1; or 
 (ii) at least one of residues 129 and 130 of SEQ ID NO: 2 in the polypeptide is deleted 
   g) a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-7;   h) a polypeptide consisting of a CD47-binding fragment of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-7; and   i) a CD47-binding variant of one of the polypeptide in g) and h) with up to 1 amino acid insertion, deletion or substitution for every 7 amino acids in length of the polypeptide.   
     
     
         52 - 53 . (canceled)