ANTI-CLDN CHIMERIC ANTIGEN RECEPTORS AND METHODS OF USE
Provided herein are novel anti-CLDN chimeric antigen receptors and methods of using the same to treat proliferative disorders.
1 . A chimeric antigen receptor comprising an anti-CLDN binding domain.
2 . The chimeric antigen receptor of claim 1 wherein the anti-CLDN binding domain comprises a scFv anti-CLDN binding domain.
3 . The chimeric antigen receptor of claim 2 wherein the scFv anti-CLDN binding domain comprises or competes for binding with an antibody comprising: a light chain variable region (VL) of SEQ ID NO: 21 and a heavy chain variable region (VH) of SEQ ID NO: 23; or a VL of SEQ ID NO: 25 and a VH of SEQ ID NO: 27; or a VL of SEQ ID NO: 29 and a VH of SEQ ID NO: 31; or a VL of SEQ ID NO: 33 and a VH of SEQ ID NO: 35; or a VL of SEQ ID NO: 37 and a VH of SEQ ID NO: 39; or a VL of SEQ ID NO: 41 and a VH of SEQ ID NO: 43; or a VL of SEQ ID NO: 45 and a VH of SEQ ID NO: 47; or a VL of SEQ ID NO: 49 and a VH of SEQ ID NO: 51; or a VL of SEQ ID NO: 53 and a VH of SEQ ID NO: 55; or a VL of SEQ ID NO: 57 and a VH of SEQ ID NO: 59.
4 . The chimeric antigen receptor of claim 3 wherein the scFv anti-CLDN binding domain comprises
(a) three complementarity determining regions of a light chain variable region (VL) of SEQ ID NO: 69 and three complementarity determining regions of a heavy chain variable region (VH) of SEQ ID NO: 71; or
(b) three complementarity determining regions of a VL of SEQ ID NO: 73 and three complementarity determining regions of a VH of SEQ ID NO: 87.
5 . The chimeric antigen receptor of claim 1 wherein the binding domain immunospecifically binds to CLDN6.
6 . The chimeric antigen receptor of claim 5 wherein the binding domain is not cross-reactive with CLDN4 or CLDN9.
7 . The chimeric antigen receptor of claim 5 wherein the binding domain is cross-reactive with CLDN4 or CLDN9.
8 . The chimeric antigen receptor of any of claims 1 to 7 comprising an intracellular domain comprising a 4-1BB signaling domain and a CD3ζ signaling domain.
9 . The chimeric antigen receptor of claim 8 further comprising a transmembrane domain comprising a human CD8 alpha hinge.
10 . A polynucleotide encoding a chimeric antigen receptor of any one of claims 1 to 9 .
11 . A vector comprising a polynucleotide of claim 10 .
12 . The vector of claim 11 wherein the vector comprises a viral vector.
13 . The vector of claim 12 wherein the viral vector comprises a lentiviral vector or a retroviral vector.
14 . A pharmaceutical composition comprising a polynucleotide of claim 10 , or a vector of any one of claims 11 to 13 .
15 . A kit for the preparation of CLDN sensitized lymphocytes comprising a pharmaceutical composition of claim 14 .
16 . An isolated host cell comprising a chimeric antigen receptor of any one of claims 1 to 9 .
17 . The isolated host cell of claim 16 wherein the host cell comprises a CLDN sensitized lymphocyte.
18 . The isolated host cell of claim 17 wherein the CLDN sensitized lymphocyte is obtained from a patient.
19 . The isolated host cell of claim 17 or 18 wherein the CLDN sensitized lymphocyte is a T cell or a NK cell.
20 . The isolated host cell of claim 19 wherein the T cell is a CD8+ T cell.
21 . The isolated host cell of claim 19 wherein the CLDN sensitized lymphocyte is a NK cell.
22 . A pharmaceutical composition comprising a host cell of any one of claims 16 to 21 .
23 . A method of treating a patient suffering from cancer comprising the step of administering a pharmaceutical composition of claim 22 to the patient.
24 . The method of claim 23 wherein the patient is suffering from a cancer selected from the group consisting of lung cancer, melanoma, breast cancer, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, neuroblastoma, rhabdomyosarcoma, leukemia and lymphoma.
25 . The method of claim 24 wherein the cancer is lung cancer and the lung cancer is small cell lung cancer.
26 . The method of claim 24 wherein the cancer is ovarian cancer.
27 . A method of reducing the frequency of cancer stem cells in a tumor cell population, wherein the method comprises contacting the tumor cell population with a pharmaceutical composition of claim 22 .
28 . A method of producing a CLDN-sensitized lymphocyte comprising the step of transforming a host cell with a polynucleotide of claim 10 .