Pd-1 targeted il-15/il-15ralpha fc fusion proteins and uses in combination therapies thereof

Abstract

The present invention is directed to novel PD-1 targeted heterodimeric Fc fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a PD-1 antibody fragment-Fc fusion protein. In some embodiments, the PD-1 targeted IL-15/Rα-Fc fusion proteins are administered to a patient to treat cancer. In some embodiments, the PD-1 targeted IL-15/Rα-Fc fusion proteins are administered in combination with a PD-1 blockade antibody such as nivolumab and/or pembrolizumab. In some embodiments, the PD-1 targeted IL-15/Rα-Fc fusion proteins do not compete with a PD-1 blockade antibody such as nivolumab and/or pembrolizumab for antigen binding.

What is claimed is: 
     
         1 . An anti-PD-1 binding domain, said anti-PD-1 binding domain comprising a variable heavy chain domain (“VH domain”) and a variable light chain domain (“VL domain”), wherein said VH domain has at least 95% amino acid sequence identity with SEQ ID NO:5 and said VL domain has at least 95% amino acid sequence identity with SEQ ID NO:6. 
     
     
         2 . The anti-PD-1 binding domain of  claim 1 , wherein said VH domain has at least 96% amino acid sequence identity with SEQ ID NO:5 and said VL domain has at least 96% amino acid sequence identity with SEQ ID NO:6. 
     
     
         3 . The anti-PD-1 binding domain of  claim 1 , wherein said VH domain has at least 97% amino acid sequence identity with SEQ ID NO:5 and said VL domain has at least 97% amino acid sequence identity with SEQ ID NO:6. 
     
     
         4 . The anti-PD-1 binding domain of  claim 1 , wherein said VH domain has at least 98% amino acid sequence identity with SEQ ID NO:5 and said VL domain has at least 98% amino acid sequence identity with SEQ ID NO:6. 
     
     
         5 . The anti-PD-1 binding domain of  claim 1 , wherein said VH domain has at least 99% amino acid sequence identity with SEQ ID NO:5 and said VL domain has at least 99% amino acid sequence identity with SEQ ID NO:6. 
     
     
         6 . The anti-PD-1 binding domain of  claim 1 , wherein said VH domain comprises a F32 amino acid substitution; and said VL domain comprises one or more amino acid substitutions selected from the group consisting of: N27dH, K30Y, and S93T, wherein the numbering is according to Kabat. 
     
     
         7 . The anti-PD-1 binding domain of  claim 6 , wherein said VL domain comprises the amino acid substitutions N27dH, K30Y, and S93T. 
     
     
         8 . The anti-PD-1 binding domain of  claim 1 , wherein said VH domain is SEQ ID NO:5 and said VL domain is SEQ ID NO:6. 
     
     
         9 . The anti-PD-1 binding domain of  claim 1 , wherein said VH domain is SEQ ID NO:5 and said VL domain is SEQ ID NO:368. 
     
     
         10 . The anti-PD-1 binding domain of  claim 1 , wherein said anti-PD-1 binding domain is an scFv further comprising a scFv linker that covalently attaches said VH domain and VL domain to form said scFv domain. 
     
     
         11 . The anti-PD-1 binding domain of  claim 10 , wherein said scFv linker is (GGGGS) n  (SEQ ID NO:10), where n is an integer between 1 and 7. 
     
     
         12 . The anti-PD-1 binding domain of  claim 10 , wherein said scFv linker is (GKPGS) n  (SEQ ID NO:28), where n is an integer between 1 and 6. 
     
     
         13 . A nucleic acid encoding the anti-PD-1 binding domain of  claim 1 . 
     
     
         14 . A nucleic acid composition comprising:
 a) a first nucleic acid encoding the VH domain of  claim 1 ; and   b) a second nucleic acid encoding the VL domain of  claim 1 .   
     
     
         15 . An expression vector comprising said nucleic acid of  claim 13 . 
     
     
         16 . An expression vector composition comprising:
 a) a first expression vector comprising said first nucleic acid of  claim 14 ; and   b) a second expression vector comprising said second nucleic acid of  claim 14 .   
     
     
         17 . A host cell comprising said expression vector of  claim 15  or said expression vector composition of  claim 16 . 
     
     
         18 . A method of producing said anti-PD-1 binding domain of  claim 1 , the method comprising: culturing the host cell of  claim 17  under conditions where said anti-PD-1 binding domain is expressed; and recovering said anti-PD-1 binding domain.