TIM-3 TARGETED HETERODIMERIC FUSION PROTEINS CONTAINING IL-15/IL-15RA Fc-FUSION PROTEINS AND TIM-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 TIM-3 antibody fragment-Fc fusion protein.

What is claimed is: 
     
         1 - 13 . (canceled) 
     
     
         14 . 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) a human IL-15 variant comprising 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; 
 iv) a second domain linker; and 
 v) a first variant Fc domain comprising CH2-CH3; and 
   b) a second monomer comprising a second variant Fc domain; and   c) means for binding the extracellular domain of human TIM-3,   wherein said first and second variant Fc domains are each a variant of a human IgG Fc domain and said first and second variant Fc domains form a heterodimer.   
     
     
         15 . The heterodimeric fusion protein according to  claim 14 , wherein said second monomer further comprises VH-CH1-hinge domain, said fusion protein further comprises a third monomer comprising VL-CL, and wherein said VH and said VL form said means for binding said extracellular domain of human TIM-3. 
     
     
         16 . The heterodimeric fusion protein according to  claim 14 , wherein said second monomer further comprises a third domain linker-scFv, wherein said scFv forms said means for binding the extracellular domain of human TIM-3. 
     
     
         17 . The heterodimeric fusion protein according to  claim 14 , wherein the hinge of the first monomer comprises amino acid substitution C220S, and wherein numbering is according to EU numbering. 
     
     
         18 . The heterodimeric fusion protein according to  claim 14 , wherein the first and second variant Fc domains each further comprise half-life extension variants M428L/N434S. 
     
     
         19 . The heterodimeric fusion protein according to  claim 14 , wherein the first variant Fc domain comprises variants L368D/K370S and the second variant Fc domain comprises variants S364K/E357Q, and wherein numbering is according to EU numbering. 
     
     
         20 . The heterodimeric fusion protein according to  claim 14 , wherein the first and second variant Fc domains each comprise variants E233P/L234V/L235A/G236del/S267K, and wherein numbering is according to EU numbering. 
     
     
         21 . The heterodimeric fusion protein according to  claim 14 , wherein the first variant Fc domain comprises variants Q295E/N384D/Q418E/N421D, and wherein numbering is according to EU numbering. 
     
     
         22 . The heterodimeric fusion protein according to  claim 14 , wherein the IL-15 variant comprises amino acid substitutions N4D/N65D, D30N/N65D, or D30N/E64Q/N65D.