Methods and compositions of a follicle stimulating hormone receptor immunoreceptor or chimeric antigen receptor

Abstract

The present invention relates to compositions and methods for diagnosing and treating diseases, disorders or conditions associated with dysregulated expression of FSHR. The invention provides novel peptides that specifically bind to Follicle-stimulation hormone receptor (FSHR).

1 .- 8 . (canceled) 
     
     
         9 . An isolated follicle-stimulating hormone receptor (FSHR) binding immunoreceptor (IR) comprising a FSHR binding domain, a transmembrane domain, and a signaling domain, wherein the FSHR binding domain comprises a follicle-stimulating hormone (FSH) or fragment thereof, a FSHR antagonist or fragment thereof, or an anti-FSHR agonist or fragment thereof. 
     
     
         10 . The isolated FSHR binding IR of  claim 9 , wherein the FSHR binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 7, 9, 11, 13, 15, 17, 19 and 21. 
     
     
         11 . The isolated FSHR binding IR of  claim 9 , wherein the transmembrane domain comprises a CD8alpha hinge and transmembrane domain. 
     
     
         12 . The isolated FSHR binding IR of  claim 9 , wherein the signaling domain comprises a CD3 signaling domain. 
     
     
         13 . The isolated FSHR binding IR of  claim 9  further comprising a costimulatory signaling region comprising an intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof. 
     
     
         14 . (canceled) 
     
     
         15 . The isolated FSHR binding IR of  claim 9 , wherein the FSHR binding IR specifically binds to FSHR expressed by tumor cells, tumor vasculature, or the combination of tumor cells and tumor vasculature. 
     
     
         16 . A cell comprising the isolated FSHR binding IR of  claim 9 . 
     
     
         17 .- 22 . (canceled) 
     
     
         23 . A method for stimulating a T cell-mediated immune response to a thyroid cell population in a mammal, the method comprising administering to a subject an effective amount of a modified cell comprising a nucleic acid sequence encoding a follicle stimulating hormone receptor (FSHR) immunoreceptor (IR), wherein the FSHR binding IR comprises a FSHR binding domain, a transmembrane domain, and a signaling domain, and wherein the FSHR binding domain comprises a follicle-stimulating hormone (FSH) or fragment thereof, a FSHR antagonist or fragment thereof, or an anti-FSHR agonist or fragments thereof. 
     
     
         24 . A method of treating a condition in a subject, the method comprising administering to the subject an effective amount of a modified cell comprising a nucleic acid sequence encoding a follicle stimulating hormone receptor (FSHR) binding immunoreceptor (IR), wherein the FSHR binding IR comprises a FSHR binding domain, a transmembrane domain, and a signaling domain, and wherein the FSHR binding domain comprises a follicle-stimulating hormone (FSH) or fragment thereof, a FSHR antagonist or fragment thereof, or an anti-FSHR agonist or fragments thereof. 
     
     
         25 . The method of  claim 24 , wherein the condition is a cancer selected from the group consisting of ovarian cancer, renal cell carcinoma, bladder cancer, kidney cancer, testicular cancer, prostate cancer, breast cancer, colon cancer, pancreatic cancer, lung cancer, liver cancer, stomach cancer and any combination thereof. 
     
     
         26 . The method of  claim 24 , wherein the modified T cell is autologous to the subject. 
     
     
         27 . The method of  claim 24 , further comprising administering an antitumor vaccine to the subject. 
     
     
         28 . The method of  claim 27 , wherein the modified T cell and the antitumor vaccine are co-administered to the subject. 
     
     
         29 . An isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR) comprising a follicle-stimulating hormone receptor (FSHR) binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the FSHR binding domain comprises an anti-FSHR antibody or a fragment thereof. 
     
     
         30 . The isolated nucleic acid sequence of  claim 29 , wherein the FSHR binding domain comprises a heavy and light chain. 
     
     
         31 . The isolated nucleic acid sequence of  claim 29 , wherein the FSHR binding domain is a human antibody, a humanized antibody, and a fragment thereof. 
     
     
         32 . The isolated nucleic acid sequence of  claim 31 , wherein the antibody or a fragment thereof is selected from the group consisting of a Fab fragment, a F(ab′) 2  fragment, a Fv fragment, and a single chain Fv (scFv). 
     
     
         33 . The isolated nucleic acid sequence of  claim 29 , wherein the FSHR binding domain specifically binds to FSHR expressed by tumor cells, tumor vasculature, or the combination of tumor cells and tumor vasculature. 
     
     
         34 . The isolated nucleic acid sequence of  claim 29 , wherein the costimulatory signaling region comprises an intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof. 
     
     
         35 . A vector comprising the isolated nucleic acid sequence of  claim 29 . 
     
     
         36 . An isolated chimeric antigen receptor (CAR) comprising a follicle-stimulating hormone receptor (FSHR) binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the FSHR binding domain comprises anti-FSHR antibody or a fragment thereof. 
     
     
         37 . The isolated CAR of  claim 36 , wherein the FSHR binding domain comprises a heavy and light chain. 
     
     
         38 . The isolated CAR of  claim 36 , wherein the FSHR binding domain is an antibody selected from the group consisting of a human antibody, humanized antibody, and fragment thereof. 
     
     
         39 . The isolated CAR of  claim 36 , wherein the FSHR binding domain is selected from the group consisting of a Fab fragment, a F(ab′) 2  fragment, a Fv fragment, and a single chain Fv (scFv). 
     
     
         40 . The isolated CAR of  claim 36 , wherein the FSHR binding domain specifically binds to FSHR expressed by tumor cells, tumor vasculature, or the combination of tumor cells and tumor vasculature. 
     
     
         41 . The isolated CAR of  claim 36 , wherein the costimulatory signaling region comprises an intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-IBB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof. 
     
     
         42 . A modified cell comprising the isolated CAR of  claim 36 . 
     
     
         43 . A modified cell comprising the nucleic acid sequence of  claim 29 . 
     
     
         44 . The modified cell of  claim 43 , wherein the FSHR binding domain specifically binds to FSHR expressed by tumor cells, tumor vasculature, or the combination of tumor cells and tumor vasculature. 
     
     
         45 . The modified cell of  claim 44 , wherein the tumor cells are from a cancer selected from the group consisting of ovarian cancer, renal cell carcinoma, bladder cancer, kidney cancer, testicular cancer, prostate cancer, breast cancer, colon cancer, pancreatic cancer, lung cancer, liver cancer, stomach cancer, and any combination thereof. 
     
     
         46 . The modified cell of  claim 43 , wherein the cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), and a regulatory T cell. 
     
     
         47 . A composition comprising the modified cell of  claim 43 . 
     
     
         48 . (canceled) 
     
     
         49 . A method for stimulating a T cell-mediated immune response to a thyroid cell population in a mammal, the method comprising administering to a subject an effective amount of the modified cell of  claim 43 . 
     
     
         50 . A method of treating a subject with cancer, the method comprising administering to the subject an effective amount of the modified cell of  claim 43 . 
     
     
         51 . The method of  claim 50 , wherein the cancer is selected from the group consisting of ovarian cancer, renal cell carcinoma, bladder cancer, kidney cancer, testicular cancer, prostate cancer, breast cancer, colon cancer, pancreatic cancer, lung cancer, liver cancer, stomach cancer and any combination thereof. 
     
     
         52 . The method of  claim 50 , wherein the modified T cell is autologous to the subject. 
     
     
         53 . The method of  claim 50  further comprising administering an antitumor vaccine to the subject. 
     
     
         54 . The method of  claim 53 , wherein the modified T cell and the antitumor vaccine are co-administered to the subject. 
     
     
         55 . An isolated nucleic acid sequence encoding the isolated CAR of  claim 36 .