JPWO2020223445A5

JPWO2020223445A5 -

Info

Publication number: JPWO2020223445A5
Application number: JP2021564537A
Authority: JP
Publication date: 2023-05-01

Claims

An isolated immunoresponsive cell comprising
(a) a first chimeric receptor comprising an extracellular antigen binding domain that binds a first antigen and a second chimeric receptor comprising an extracellular antigen binding domain that binds a second antigen ; or
(b) a chimeric receptor comprising two or more antigen binding domains, wherein each of said two or more antigen binding domains binds an antigen and each antigen binding domain binds a separate antigen;
including
Each antigen is FLT3, CD33, CLEC12A, MS4A3, VSTM1, LAT2, MLC1, CD131, GAPT, PRAM1, SLC22A16, SLC17A9, SPNS3, ADGRE2, IL3RA, CD117, CD93, IL1RAP, CD244, CCR1, LILRB2, PIEZO1, CD38, selected from the group consisting of EMB, MYADM, LILRA2, CD300LF, and CD70;
wherein said first antigen is different from said second antigen;
Said isolated immunoresponsive cell.

wherein the first antigen is FLT3, and the extracellular antigen-binding domain of the first chimeric receptor comprises
(a) a VH comprising the amino acid sequence of SEQ ID NO:3 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO:4 or a sequence at least 90% identical thereto;
(b) a VH comprising the amino acid sequence of SEQ ID NO: 1 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 2 or a sequence at least 90% identical thereto;
(c) a VH comprising the amino acid sequence of SEQ ID NO:5 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO:6 or a sequence at least 90% identical thereto;
(d) a VH comprising the amino acid sequence of SEQ ID NO:7 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO:8 or a sequence at least 90% identical thereto;
(e) a VH comprising the amino acid sequence of SEQ ID NO:9 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO:10 or a sequence at least 90% identical thereto;
(f) a VH comprising the amino acid sequence of SEQ ID NO: 11 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 12 or a sequence at least 90% identical thereto;
(g) a VH comprising the amino acid sequence of SEQ ID NO: 13 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 14 or a sequence at least 90% identical thereto, and (h) an amino acid sequence of SEQ ID NO: 15 or a VH comprising a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 16 or a sequence at least 90% identical thereto
2. The isolated immunoresponsive cell of claim 1, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL) selected from the group consisting of:

i) said second antigen is CD33 and said extracellular antigen binding domain of said second chimeric receptor is
(a) a VH comprising the amino acid sequence of SEQ ID NO: 17 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 18 or a sequence at least 90% identical thereto, and (b) the amino acid sequence of SEQ ID NO: 19 or a VH comprising a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 20 or a sequence at least 90% identical thereto
a heavy chain variable domain (VH) and a light chain variable domain (VL) selected from the group consisting of; or ii) said second antigen is CLEC12A;
(a) a VH comprising the amino acid sequence of SEQ ID NO:21 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO:22 or a sequence at least 90% identical thereto;
(b) a VH comprising the amino acid sequence of SEQ ID NO:23 or a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO:24 or a sequence at least 90% identical thereto, and (c) an amino acid sequence of SEQ ID NO:25 or a VH comprising a sequence at least 90% identical thereto, and a VL comprising the amino acid sequence of SEQ ID NO: 26 or a sequence at least 90% identical thereto
a heavy chain variable domain (VH) and a light chain variable domain (VL) selected from the group consisting of
3. The isolated immunoresponsive cell of claim 2.

each chimeric receptor is a CAR ,
Each CAR
i) a CD3 zeta chain intracellular signaling domain, optionally each CAR further comprising one or more additional intracellular signaling domains, said one or more additional intracellular signaling domains comprising CD97; intracellular signaling domain, CD11a-CD18 intracellular signaling domain, CD2 intracellular signaling domain, ICOS intracellular signaling domain, CD27 intracellular signaling domain, CD154 intracellular signaling domain, CD8 intracellular signaling domain, OX40 intracellular signaling domain, 4-1BB intracellular signaling domain, CD28 intracellular signaling domain, ZAP40 intracellular signaling domain, CD30 intracellular signaling domain, GITR intracellular signaling domain, HVEM intracellular signaling domain , the DAP10 intracellular signaling domain, the DAP12 intracellular signaling domain, the MyD88 intracellular signaling domain, and the 2B4 intracellular signaling domain; and/or ii) a transmembrane domain, wherein the transmembrane The domains are CD8 transmembrane domain, CD28 transmembrane domain, CD3 zeta chain transmembrane domain, CD4 transmembrane domain, 4-1BB transmembrane domain, OX40 transmembrane domain, ICOS transmembrane domain, CTLA-4 transmembrane domain, PD -1 transmembrane domain, LAG-3 transmembrane domain, 2B4 transmembrane domain, and BTLA transmembrane domain, and/or iii) a spacer region between said antigen binding domain and said transmembrane domain wherein the spacer region has an amino acid sequence selected from the group consisting of SEQ ID NOS: 55-64;
The isolated immunoresponsive cell of any one of claims 1-3 .

5. Any one of claims 1-4 , wherein said cell further comprises an inhibitory chimeric receptor comprising an antigen binding domain, optionally said inhibitory chimeric receptor inhibits one or more activities of said cell. 13. The isolated immunoresponsive cell of paragraph.

wherein said inhibitory chimeric receptor binds to an antigen expressed on a non-tumor cell, optionally wherein said antigen expressed on a non-tumor cell is selected from brain, nervous tissue, endocrine, bone, bone marrow, immune system, 6. The tissue of claim 5 , derived from a tissue selected from the group consisting of endothelial tissue, muscle, lung, liver, gallbladder, pancreas, gastrointestinal tract, kidney, bladder, male reproductive organs, female reproductive organs, fat, soft tissue, and skin. Isolated immunoresponsive cells.

said inhibitory chimeric receptor is EMCN, JAM2, MS4A15, C4BPA, TRPM1, SCTR, SLC2A2, KCNQ2, PERP, WLS, FFAR2, PTPRB, NCKAP1, MPZL2, PLSCR4, TMEM47, ADGRL4, MET, BACE2, ATP8B1, LIFR, an antigen selected from the group consisting of ART4, CALCRL, CNTNAP3, PCDH9, IL18R1, SLC8A3, CDH26, TMEM163, ABCA13, CACHD1, CYYR1, ABCB1, ADGRG6, ATP9A, CALN1, CDCP1, IL12RB2, SLC16A14, TMEM136, and TMEM200A combined with 7. The isolated immunoresponsive cell of claim 5 or claim 6 , wherein the immunoresponsive cell is.

8. The isolation of any one of claims 5-7 , wherein said inhibitory chimeric receptor comprises an antigen binding domain comprising a single chain variable fragment (scFv), said scFv being derived from an anti-EMCN antibody. immunoresponsive cells.

said antigen binding domain of said first chimeric receptor, said antigen binding domain of said second chimeric receptor, and/or said antigen binding domain of said inhibitory chimeric receptor comprises one or more single chain variable fragments (scFv), each of said one or more scFvs comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), optionally wherein said VH and VL are separated by a peptide linker; Optionally, the isolated immunoresponsive cell of any one of claims 5-8 , wherein said peptide linker comprises the amino acid sequence of SEQ ID NO:27.

10. The isolated immunoresponsive cell of Claim 9 , wherein each of said one or more scFv binds a distinct epitope on the same antigen.

11. The one or more scFv of claim 9 or 10, wherein each of said one or more scFv is separated by a peptide linker, optionally said peptide linker comprising an amino acid sequence of GGGGSGGGGSGGGGS (SEQ ID NO: 27) or EAAAAKEAAAAKEAAAAAKEAAAK (SEQ ID NO: 74). of isolated immunocompetent cells.

said cells are T cells, natural killer (NK) cells, cytotoxic T lymphocytes (CTL), regulatory T cells, natural killer T (NKT) cells, bone marrow cells, macrophages, human embryonic stem cells (ESC), selected from the group consisting of ESC-derived cells, pluripotent stem cells, and induced pluripotent stem cells (iPSCs), and iPSC-derived cells;
optionally, said immunoresponsive cells are allogeneic;
The isolated immunoresponsive cell of any one of claims 1-11 .

A pharmaceutical composition comprising an effective amount of the isolated immunoresponsive cells of any one of claims 1-12 , and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a combination thereof. composition.

A method for providing anti-tumor immunity in a subject comprising a therapeutically effective amount of any of the isolated immunoresponsive cells of any one of claims 1-12 or the pharmaceutical composition of claim 13 . Medicine .

for treating or preventing bone marrow damage in a subject comprising a therapeutically effective amount of any of the isolated immunoreactive cells of any one of claims 1-12 or the pharmaceutical composition of claim 13 . a medicament of
Optionally, said myelopathy is myelodysplastic syndrome, myeloproliferative neoplasm, chronic myelomonocytic leukemia, acute myeloid leukemia (AML), acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia is leukemia, chronic myelogenous leukemia, and polycythemia vera,
Said medicament .