JPWO2020043152A5

JPWO2020043152A5 -

Info

Publication number: JPWO2020043152A5
Application number: JP2021510019A
Authority: JP
Publication date: 2022-09-01

Claims

An isolated antibody or antigen-binding fragment that specifically binds to mesothelin, comprising:
i. in complementarity determining region 1 (CDR1), CDR2 and CDR3,
a. SEQ ID NOs: 34, 102, and 170, respectively;
b. SEQ ID NOs: 54, 122, and 190, respectively;
c. SEQ ID NOs: 55, 123, and 191, respectively;
d. SEQ ID NOs: 61, 129, and 197, respectively;
e. SEQ ID NOS: 31, 99, and 167, respectively;
f. SEQ ID NOs: 32, 100, and 168, respectively;
g. SEQ ID NOs: 33, 101, and 169, respectively;
h. SEQ ID NOs: 35, 103, and 171, respectively;
i. SEQ ID NOs: 36, 104, and 172, respectively;
j. SEQ ID NOs: 37, 105, and 173, respectively;
k. SEQ ID NOs: 38, 106, and 174, respectively;
l. SEQ ID NOs: 39, 107, and 175, respectively;
m. SEQ ID NOs: 40, 108, and 176, respectively;
n. SEQ ID NOS: 41, 109, and 177, respectively;
o. SEQ ID NOS: 42, 110, and 178, respectively;
p. SEQ ID NOs: 43, 111, and 179, respectively;
q. SEQ ID NOs: 44, 112, and 180, respectively;
r. SEQ ID NOs: 45, 113, and 181, respectively;
s. SEQ ID NOs: 46, 114, and 182, respectively;
t. SEQ ID NOs: 47, 115, and 183, respectively;
u. SEQ ID NOs: 48, 116, and 184, respectively;
v. SEQ ID NOs: 49, 117, and 185, respectively;
w. SEQ ID NOs: 50, 118, and 186, respectively;
x. SEQ ID NOs: 51, 119, and 187, respectively;
y. SEQ ID NOS: 52, 120, and 188, respectively;
z. SEQ ID NOs: 53, 121, and 189, respectively;
aa. SEQ ID NOs: 56, 124, and 192, respectively;
bb. SEQ ID NOs: 57, 125, and 193, respectively;
cc. SEQ ID NOS: 58, 126, and 194, respectively;
dd. SEQ ID NOS: 59, 127, and 195, respectively;
ee. SEQ ID NOs: 60, 128, and 196, respectively;
ff. SEQ ID NOs: 62, 130, and 198, respectively;
gg. SEQ ID NOs: 63, 131, and 199, respectively;
hh. SEQ ID NOs: 64, 132, and 200, respectively;
ii. SEQ ID NOs: 65, 133, and 201, respectively;
jj. SEQ ID NOs: 66, 134, and 202, respectively;
kk. SEQ ID NOs: 67, 135, and 203, respectively, or
ll. a single domain antibody (sdAb) comprising complementarity determining regions having the polypeptide sequences of SEQ ID NOs: 68, 136 and 204, respectively; or
ii. heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3,
a. SEQ ID NOS: 1, 69, 137, 2, 70, and 138, respectively;
b. SEQ ID NOs: 19, 87, 155, 20, 88, and 156, respectively;
c. SEQ ID NOs: 23, 91, 159, 24, 92, and 160, respectively;
d. SEQ ID NOs: 25, 93, 161, 26, 94, and 162, respectively;
e. SEQ ID NOs: 27, 95, 163, 28, 96, and 164, respectively;
f. SEQ ID NOs: 29, 97, 165, 30, 98, and 166, respectively;
g. SEQ ID NOs: 3, 71, 139, 4, 72, and 140, respectively;
h. SEQ ID NOs: 5, 73, 141, 6, 74, and 142, respectively;
i. SEQ ID NOs: 7, 75, 143, 8, 76, and 144, respectively;
j. SEQ ID NOs: 9, 77, 145, 10, 78, and 146, respectively;
k. SEQ ID NOs: 11, 79, 147, 12, 80, and 148, respectively;
l. SEQ ID NOs: 13, 81, 149, 14, 82, and 150, respectively;
m. SEQ ID NOs: 15, 83, 151, 16, 84, and 152, respectively;
n. SEQ ID NOs: 17, 85, 153, 18, 86, and 154, respectively, or
o. single chain variable fragments (scFv) comprising complementarity determining regions having the polypeptide sequences of SEQ ID NOs: 21, 89, 157, 22, 90 and 158, respectively;
An isolated antibody or antigen-binding fragment.

wherein the isolated antibody or antigen-binding fragment comprises
i. said single domain antibody comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs:221-258 and SEQ ID NOs:420-428; or
ii. 2. The isolated antibody or antigen-binding fragment of claim 1, comprising said single chain variable fragment comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs:205-220.

An isolated polynucleotide comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises
(a) an extracellular domain comprising an antigen-binding fragment comprising the isolated antibody or antigen-binding fragment of claim 1 or 2;
(b) a transmembrane domain;
(c) an intracellular signaling domain; and
An isolated polynucleotide comprising:

4. The isolated polynucleotide of claim 3, wherein said CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:358-367 and SEQ ID NOs:445-447.

An isolated polynucleotide comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises
(a) an extracellular domain comprising a first polypeptide that specifically binds to follicle-stimulating hormone receptor (FSHR) and an antigen-binding fragment comprising the isolated antibody or antigen-binding fragment of claim 1 or 2;
(b) a transmembrane domain;
(c) an intracellular signaling domain; and
An isolated polynucleotide comprising:

said extracellular domain of said CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 348-357; or said CAR is selected from the group consisting of SEQ ID NOs: 370-379 and SEQ ID NOs: 448-450 6. The isolated polynucleotide of claim 5, comprising the amino acid sequence of

The isolated polynucleotide further comprises a second nucleotide sequence encoding a second chimeric antigen receptor (CAR), wherein the second CAR is
(a) an extracellular domain comprising a polypeptide that specifically binds to the follicle stimulating hormone receptor (FSHR);
(b) a transmembrane domain;
(c) an intracellular signaling domain; and
4. The isolated polynucleotide of claim 3, comprising:

Said polypeptide that specifically binds to FSHR comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 319-331, or said isolated polynucleotide comprises SEQ ID NOS: 380-389 and SEQ ID NOS: 451- 8. The isolated polynucleotide of claim 7, comprising an amino acid sequence selected from the group consisting of 453.

further comprising a second nucleotide sequence encoding a fusion protein, said fusion protein, from N-terminus to C-terminus, a first polypeptide that specifically binds to the follicle-stimulating hormone receptor (FSHR); and the CD3-gamma chain. 4. The isolated polynucleotide of claim 3, comprising an extracellular domain, a transmembrane domain and an intracellular domain of a CD3 polypeptide selected from the group consisting of: , CD3-delta chain and CD3-epsilon chain.

10. The isolated polynucleotide of claim 9, wherein said isolated polynucleotide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:454-456.

further comprising a third nucleotide sequence encoding a dominant negative form of an inhibitor of immune cell cellular immune response, wherein said inhibitor of immune cell cellular immune response is transforming growth factor-β (TGF-β) receptor; 11. The isolated polynucleotide of any one of claims 3-10, which is a body.

12. The isolated polynucleotide of claim 11, wherein said dominant negative form of said inhibitor comprises the amino acid sequence of SEQ ID NO:347.

The isolated polynucleotide is a protein having an amino acid sequence selected from the group consisting of SEQ ID NOs: 390-399, 400-409, 410-419, 460-462, 463-465, 466-468 and 469-471 13. The isolated polynucleotide of claim 11 or 12, which encodes a

14. An isolated nucleic acid encoding the isolated antibody or antigen-binding fragment of claim 1 or 2, or the isolated polynucleotide of any one of claims 3-13.

A vector comprising the isolated nucleic acid of claim 14 .

14. An engineered immune cell expressing the CAR or TCR complex encoded by the isolated polynucleotide of any one of claims 3-13.

17. The engineered immune cell of Claim 16, wherein said engineered immune cell is selected from the group consisting of cytotoxic T cells, helper T cells, natural killer T cells, γδ T cells, and NK cells.

18. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of claim 1 or 2, or the engineered immune cell of claim 16 or 17, and a pharmaceutically acceptable carrier.

A medicament for treating cancer in an individual, wherein the isolated antibody or antigen-binding fragment of claim 1 or 2, or claim 18, in an amount effective to treat said cancer. Pharmaceuticals, including pharmaceutical compositions.

The cancer is ovarian cancer, primary peritoneal cancer, pancreatic ductal adenocarcinoma (PDA), malignant pleural mesothelioma (MPM), lung adenocarcinoma, triple negative breast cancer, endometrial cancer, biliary tract cancer, gastric cancer, or pediatric acute bone marrow 20. The medicament according to claim 19, which is sexual leukemia.