LAG-3 TARGETED HETERODIMERIC FUSION PROTEINS CONTAINING IL-15/IL-15RA Fc-FUSION PROTEINS AND LAG-3 ANTIGEN BINDING DOMAINS

Abstract

The present invention is directed to novel targeted heterodimeric fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a LAG-3 antibody fragment-Fc fusion protein.

What is claimed is: 
     
         1 . A heterodimeric fusion protein comprising:
 a) a first monomer comprising, from N-to C-terminal:
 i) an IL-15Rα(sushi) domain; 
 ii) a first domain linker; 
 iii) an IL-15 variant; 
 iv) a hinge; and 
 v) a first variant Fc domain comprising CH2-CH3; and 
   b) a second monomer comprising, from N-to C-terminal, VH-CH1-hinge-CH2-CH3, wherein the CH2-CH3 is a second variant Fc domain; and   c) a third monomer comprising a VL-CL,   wherein the VH and VL are a variable heavy domain and a variable light domain, respectively, that form a human LAG-3 antigen binding domain,   wherein the first variant Fc domain comprises skew variants L368D/K370S and the second variant Fc domain comprises skew variants S364K/E357Q,   wherein the first and second variant Fc domains each comprise FcKO variants E233P/L234V/L235A/G236del/S267K,   wherein the first variant Fc domain comprises pI variants Q295E/N384D/Q418E/N421D, and wherein numbering is according to EU numbering.   
     
     
         2 . A heterodimeric fusion protein according to  claim 1 , wherein the hinge of the first monomer comprises amino acid substitution C220S, and wherein numbering is according to EU numbering. 
     
     
         3 . A heterodimeric fusion protein according to  claim 1  or  2 , wherein the first and second variant Fc domains each further comprise half-life extension variants 
     
     
         4 . A heterodimeric fusion protein according to any one of  claims 1  to  3 , wherein the IL-15 variant comprises an amino acid substitution(s) selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D, Q108E, N4D/N65D, D30N/N65D, and D30N/E64Q/N65D. 
     
     
         5 . A heterodimeric fusion protein according to  claim 4 , wherein the IL-15 variant comprises amino acid substitutions N4D/N65D, D30N/N65D, or D30N/E64Q/N65D 
     
     
         6 . A heterodimeric fusion protein according to any one of  claims 1  to  5 , wherein the VH and VL are the variable heavy domain and variable domain of any of the LAG-3 antigen binding domains in  FIGS. 12 and 13 . 
     
     
         7 . A heterodimeric fusion protein according to  claim 6 , wherein the LAG-3 antigen binding domain is selected from 2A11_H1.144_L2.142 and 7G8_H3.30_L1.34. 
     
     
         8 . A heterodimeric fusion protein according to  claim 1 , wherein the heterodimeric fusion protein is selected from the group consisting of: XENP27972, XENP27973, XENP27977, XENP27978, XENP029486, XENP029487, XENC1000, XENC1001, XENC1002, XENC1003, XENC1004 and XENC1005. 
     
     
         9 . A nucleic acid composition comprising:
 a) a first nucleic acid encoding said first monomer of any of  claims 1  to  8 ;   b) a second nucleic acid encoding said second monomer of any of  claims 1  to  8 ;   a) a third nucleic acid encoding said third monomer of any of  claims 1  to  8 ;   
       respectively. 
     
     
         10 . An expression vector composition comprising:
 a) a first expression vector comprising said first nucleic acid of  claim 9 ;   b) a second expression vector comprising said second nucleic acid of  claim 9 ; and   c) a third expression vector comprising said third nucleic acid of  claim 9 .   
     
     
         11 . A host cell comprising the expression vector composition according to  claim 10 . 
     
     
         12 . A method of making a heterodimeric fusion protein comprising culturing the host cell of  claim 11  and recovering the heterodimeric fusion protein from the cell culture.