Polypeptide constructs and uses thereof

Abstract

The present invention provides a polypeptide construct comprising a peptide or polypeptide signaling ligand linked to an antibody or antigen binding portion thereof which binds to a cell surface-associated antigen, wherein the ligand comprises at least one amino acid substitution or deletion which reduces its potency on cells lacking expression of said antigen.

1 . A polypeptide construct, comprising an antibody that specifically binds to CD38, or antigen binding portion thereof, linked to an attenuated interferon α2b (IFN α2b) comprising at least one attenuating amino acid substitution. 
     
     
         2 . The polypeptide construct according to  claim 1 , wherein the at least one attenuating substitution is selected is selected from the group consisting of R144A (SEQ ID NO: 30), R144S (SEQ ID NO: 40), R144T (SEQ ID NO: 41), R144Y (SEQ ID NO: 43), R144I (SEQ ID NO: 35), R144L (SEQ ID NO: 37), A145D (SEQ ID NO: 44), A145G (SEQ ID NO: 46), A145H (SEQ ID NO: 47), A145Y (SEQ ID NO: 58), A145K (SEQ ID NO: 49), R33A, +YNS (SEQ ID NO: 65), R33A (SEQ ID NO: 16) and R144A+YNS (SEQ ID NO: 68). 
     
     
         3 . The polypeptide construct according to  claim 1 , wherein the attenuated IFN α2b comprises the substitution A145D. 
     
     
         4 . The polypeptide construct according to  claim 3 , wherein the attenuated IFN α2b has the amino acid sequence of SEQ ID NO: 44. 
     
     
         5 . The polypeptide construct according to  claim 1 , wherein the antibody that specifically binds to CD38 comprises a heavy chain comprising an HCDR1 having the amino acid sequence DSVMN, an HCDR2 having the amino acid sequence WIDPEYGRTDVAEKFKK, an HCDR3 having the amino acid sequence TKYNSGYGFPY, an LCDR1 having the amino acid sequence KASQNVDSDVD, an LCDR2 having the amino acid sequence KASNRYT, and an LCDR3 having the amino acid sequence MQSNTHPRT. 
     
     
         6 . The polypeptide construct according to  claim 5 , wherein the attenuated IFN α2b comprises the substitution A145D. 
     
     
         7 . The polypeptide construct according to  claim 1 , wherein the antibody that specifically binds to CD38 comprises a variable light chain and variable heavy chain pair selected from the group consisting of SEQ ID NO: 384 and SEQ ID NO: 385, SEQ ID NO: 386 and SEQ ID NO: 387, SEQ ID NO: 388 and SEQ ID NO: 389, SEQ ID NO: 390 and SEQ ID NO: 391, SEQ ID NO: 392 and SEQ ID NO: 393, SEQ ID NO: 394 and SEQ ID NO: 395, and SEQ ID NO: 396 and SEQ ID NO: 397. 
     
     
         8 . The polypeptide according to  claim 1 , wherein the antibody that specifically binds to CD38 comprises a variable light chain and variable heavy chain pair selected from the group consisting of SEQ ID NO: 134 and SEQ ID NO: 135, SEQ ID NO: 218 and SEQ ID NO: 219, SEQ ID NO: 222 and SEQ ID NO: 223, SEQ ID NO: 226 and SEQ ID NO: 227, SEQ ID NO: 234 and SEQ ID NO: 235, SEQ ID NO: 242 and SEQ ID NO: 243, and SEQ ID NO: 250 and SEQ ID NO: 251. 
     
     
         9 . The polypeptide construct according to  claim 7 , wherein the attenuated IFN α2b comprises the substitution A145D. 
     
     
         10 . The polypeptide construct according to  claim 8 , wherein the attenuated IFN α2b comprises the substitution A145D. 
     
     
         11 . The polypeptide construct according to  claim 7 , wherein the attenuated IFN α2b has the amino acid sequence of SEQ ID NO: 44. 
     
     
         12 . The polypeptide construct according to  claim 1 , wherein the attenuated IFN α2b is linked to the antibody or antigen binding portion thereof via a peptide bond. 
     
     
         13 . The polypeptide construct according to  claim 1 , wherein the attenuated IFN α2b is linked to the antibody or antigen binding portion thereof directly, or via a linker of 1 to 20 amino acids in length. 
     
     
         14 . The polypeptide construct according to  claim 1 , wherein the antibody or antigen binding portion thereof comprises a light chain and the attenuated IFN α2b is linked to the C-terminus of the light chain. 
     
     
         15 . The polypeptide construct according to  claim 1 , wherein the antibody or antigen binding portion thereof comprises a heavy chain and the attenuated IFN α2b is linked to the C-terminus of the heavy chain. 
     
     
         16 . The polypeptide construct according to  claim 1 , wherein the antibody or antigen binding portion thereof specifically binds to CD38 with an affinity of from 50 nM to 1 pM, from 25 nM to 1 pM, from 10 nM to 1 pM, or from 5 nM to 1 pM. 
     
     
         17 . The polypeptide construct according to  claim 1 , wherein the antigen binding portion of the antibody comprises an Fab. 
     
     
         18 . The polypeptide construct according to  claim 1 , wherein the construct has an Antigen-Specificity Index of greater than 50. 
     
     
         19 . The polypeptide construct according to  claim 1 , wherein the antibody comprises a human IgG1 heavy chain constant domain. 
     
     
         20 . The polypeptide construct according to  claim 1 , wherein the antibody comprises a human IgG4 heavy chain constant domain.