Galectin-9 Specific Binding Agents for Use in Treating Cancer

Abstract

This disclosure relates to uses of galectin-9 specific binding agents and chimeric antigen receptors in methods of treating cancer such as hematological cancers or solid tumors. In certain embodiments, the galectin-9 specific binding agent is a TIM3, CD44, CD40, CLEC7a (Dectin-1), or CD137 (4- IBB) extracellular domain, an anti-galectin-9 antibody, specific binding single chain antibody, fragment, or variant thereof. In certain embodiments, cancer treatment is a cell-based therapy using chimeric antigen receptors having a galectin-9 targeting sequence.

Description

Claims

1. A method of treating cancer comprising isolating T cells from a subject;transfecting the T cells with a vector encoding a chimeric antigen receptor comprising a galectin-9 specific binding agent;culturing the T cells under conditions such that the galectin-9 specific chimeric antigen receptor is expressed on the surface of the T cells; andadministering an effective of amount of the T cells expressing the galectin-9 specific chimeric antigen receptor to the subject.

2. The method of claim 1, wherein the galectin-9 specific binding agent has a TIM3 extracellular domain amino acid sequence.

3. The method of claim 1, wherein the TIM3 extracellular domain has amino acid sequence SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYW TSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPT RQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATI RIG (SEQ ID NO: 1) or variants thereof.

4. The method of claim 1, wherein the galectin-9 specific binding agent is a single chain antibody having amino acid sequence MKCSWGIFFLLSVTAGVHSKVQLQQSGAELVKPGASVKLSCKASGYTFTDYTIHWVKQ RSGQGLEWIGWFYPGSHSIKYNEQFKDRATLTADKSSSTVYMELSRLTSEDSAVYFCTR HGGYDGFDYWGQGTTLTVSSAKTTPPSVYPLGGGGSGGGGSGGGGSLDGGKMDSQAQ VLMLLLLWVSGTCGDIVMSQSPSSLAVSVGEKITMSCKSSQSLFYSTNQKNYLAWYQQ KPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYYFPYTF GGGTKLEIKRADAAPTVSIFPPSS (SEQ ID NO: 10) or variants thereof.

5. The method of claim 1, wherein the galectin-9 specific binding agent is a single chain antibody having amino acid sequence a single chain antibody having amino acid sequence MGWSFIILLSVTAGVHSKVQLQQSGAELVKPGASVKLSCKASGYTFTEYTIHWVKQRSG QGLEWIGWFYPGSGSMEYNEKFDKATLTADNSSSTVYMELSRLTSEDSAVYFCERHGG YDGFDYWGQGTTLTVSSAKTTPPSVYPLIFLEDLLQYSQLPWKIDVLLLFSQDFQAVYG GGGSGGGGSGGGGSLDGGKMDSQAQVLMLLLLWVSGTCGDIVMSQSPSSLAVSVGEK VTMSCKSSQSLLYSNNQKNYLAWYQQKPGQSPKLLIYWASTRGSGVPDRFTGSGSGTD FTLTISSVKAEDLAIYYCQQYYSYPFTFGGGTKLEIKRADAAPTVSIFPPSS (SEQ ID NO: 17) or variants thereof.

6. The method of claim 1, wherein the chimeric antigen receptor comprises CD28 and CD3zeta.

7. The method of claim 1, wherein the subject is diagnosed with a hematological cancer or metastatic tumor.

8. The method of claim 1, wherein the subject has a body mass index of greater than 30.

9. The method of claim 1, further comprising administering another anticancer agent to the subject.

10. A vector comprising nucleic acid encoding a chimeric antigen receptor wherein the chimeric antigen receptor comprises polypeptide segment that specifically binds galectin-9.

11. The vector of claim 10 wherein the polypeptide segment that specifically binds galectin-9 has a TIM3 extracellular domain amino acid sequence.

12. The vector of claim 11 wherein the TIM3 extracellular domain has amino acid sequence SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERD VNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAK VTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDSRLANDLR DSGATIRIG (SEQ ID NO: 1) or variants thereof.

13. The vector of claim 10 wherein the polypeptide segment that specifically binds galectin-9 is a single chain antibody having amino acid sequence MKCSWGIFFLLSVTAGVHSKVQLQQSGAELVKPGASVKLSCKASGYTFTDYTIHWVKQ RSGQGLEWIGWFYPGSHSIKYNEQFKDRATLTADKSSSTVYMELSRLTSEDSAVYFCTR HGGYDGFDYWGQGTTLTVSSAKTTPPSVYPLGGGGSGGGGSGGGGSLDGGKMDSQAQ VLMLLLLWVSGTCGDIVMSQSPSSLAVSVGEKITMSCKSSQSLFYSTNQKNYLAWYQQ KPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYYFPYTF GGGTKLEIKRADAAPTVSIFPPSS (SEQ ID NO: 10) or variants thereof.

14. The vector of claim 10 wherein polypeptide segment that specifically binds galectin-9 is a single chain antibody having amino acid sequence a single chain antibody having amino acid sequence MGWSFIILLSVTAGVHSKVQLQQSGAELVKPGASVKLSCKASGYTFTEYTIHWVKQRSG QGLEWIGWFYPGSGSMEYNEKFDKATLTADNSSSTVYMELSRLTSEDSAVYFCERHGG YDGFDYWGQGTTLTVSSAKTTPPSVYPLIFLEDLLQYSQLPWKIDVLLLFSQDFQAVYG GGGSGGGGSGGGGSLDGGKMDSQAQVLMLLLLWVSGTCGDIVMSQSPSSLAVSVGEK VTMSCKSSQSLLYSNNQKNYLAWYQQKPGQSPKLLIYWASTRGSGVPDRFTGSGSGTD FTLTISSVKAEDLAIYYCQQYYSYPFTFGGGTKLEIKRADAAPTVSIFPPSS (SEQ ID NO: 17) or variants thereof.

15. A non-embryonic cell comprising a vector of claim 10.

16. A method of treating cancer comprising administering an effective amount of a galectin-9 specific binding agent to a subject in need thereof diagnosed with a body mass index above 30.

17. The method of claim 16 wherein the specific binding agent is a galectin-9 antibody, single-chain antibody, or fragment thereof.

18. The method of claim 15 wherein the specific binding agent is the extracellular domain of TIM3, CD44, CD40, CLEC7a (Dectin-1), or CD137 (4-1BB).

19. The method of claim 15 wherein the galectin-9 specific binding agent is administered in combination with another anticancer agent.

20. The method of claim 19 wherein the anticancer agent is an anti-PD-1 antibody, anti-PD-1L antibody, or an anti-CTLA-4 antibody.