FLT3L-Fc FUSION PROTEINS AND METHODS OF USE

Abstract

Provided are FLT3L-Fc fusion proteins, polynucleotides encoding such fusion proteins, expression cassettes, vectors, cells and kits comprising such fusion proteins, and methods of using.

1 .- 350 . (canceled) 
     
     
         351 . A fusion protein comprising: a human fms related tyrosine kinase 3 ligand (FLT3L) extracellular domain operably linked to an immunoglobulin fragment crystallizable region (Fc region), wherein the fusion protein comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-18 and 21-27, and wherein
 i. at least 5 amino acids are truncated from the C-terminus of the FLT3L extracellular domain; and/or   ii. the Fc region does not comprise a hinge region.   
     
     
         352 . The fusion protein of  claim 351 , comprising an amino acid sequence of SEQ ID NO:1. 
     
     
         353 . The fusion protein of  claim 351 , comprising an amino acid sequence of SEQ ID NO:9. 
     
     
         354 . The fusion protein of  claim 351 , comprising an amino acid sequence of SEQ ID NO:6. 
     
     
         355 . The fusion protein of  claim 351 , comprising an amino acid sequence of SEQ ID NO:14. 
     
     
         356 . The fusion protein of  claim 351 , wherein the Fc region is from a human IgG1 and does not comprise a hinge region. 
     
     
         357 . The fusion protein of  claim 356 , wherein the C-terminus of the FLT3L extracellular domain is not truncated. 
     
     
         358 . The fusion protein of  claim 351 , wherein the Fc region is from a human IgG4 and at least 5 amino acids are truncated from the C-terminus of the FLT3L extracellular domain. 
     
     
         359 . The fusion protein of  claim 358 , wherein the Fc region comprises a hinge region. 
     
     
         360 . The fusion protein of  claim 351 , wherein the Fc region comprises the following amino acids at the indicated positions (EU index numbering):
 i. Tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (YTE); or   ii. Leucine at position 428 and serine at position 434 (LS).   
     
     
         361 . The fusion protein of  claim 351 , wherein the fusion protein has a serum half-life of at least about 7 days. 
     
     
         362 . A homodimer comprising two identical fusion proteins of  claim 351 . 
     
     
         363 . A heterodimer comprising two non-identical fusion proteins of  claim 351 . 
     
     
         364 . A polynucleotide encoding a fusion protein of  claim 351 . 
     
     
         365 . An expression cassette comprising one or more regulatory sequences operably linked to the polynucleotide of  claim 364 . 
     
     
         366 . A vector comprising the polynucleotide of  claim 364 . 
     
     
         367 . A lipid nanoparticle (LNP) comprising the polynucleotide of  claim 364 . 
     
     
         368 . A cell or population of cells comprising the polynucleotide of  claim 364 , wherein the cell expresses or the population of cells express the fusion protein of  claim 351 . 
     
     
         369 . A pharmaceutical composition comprising the fusion protein of  claim 351  and a pharmaceutically acceptable carrier. 
     
     
         370 . A method of promoting, inducing and/or increasing the expansion and/or proliferation of a cell or a population of cells that express fms related tyrosine kinase 3 (FLT3, CD135), comprising contacting the cell or population of cells in vitro with an effective amount of the fusion protein of  claim 351 . 
     
     
         371 . A method of preventing, reducing and/or inhibiting the recurrence, growth, proliferation, migration and/or metastasis of a cancer cell or population of cancer cells in a subject in need thereof, comprising administering to the subject an effective amount of the fusion protein of  claim 351 . 
     
     
         372 . A method of enhancing, promoting, and/or increasing the tumor infiltration of T-cells and/or NK cells in a subject in need thereof, comprising administering to the subject an effective amount of the fusion protein of  claim 351 . 
     
     
         373 . A method of enhancing, improving, and/or increasing the response to an anticancer therapy in a subject in need thereof, comprising co-administering to the subject (1) an effective amount of the fusion protein of  claim 351 ; and (2) an effective amount of an anticancer agent. 
     
     
         374 . A method of enhancing, improving, and/or increasing the response to an immune checkpoint protein in a subject in need thereof, comprising co-administering to the subject (1) an effective amount of the fusion protein of  claim 351 ; and (2) an effective amount of the immune checkpoint protein. 
     
     
         375 . A method of treating or preventing a virus infection comprising administering an effective amount of the fusion protein of  claim 351  to a subject in need thereof. 
     
     
         376 . A kit comprising one or more unitary doses of the fusion protein of  claim 351 .