Granted Patent
B2
US 12,649,792 · App. 17/609,309 · Granted Jun 9, 2026
Bispecific antibodies against CHI3L1 and PD1 with enhanced T cell-mediated cytotoxic effects on tumor cells
Inventors:
Jack A. Elias (Providence, RI); Chun Geun Lee (Providence, CT); Suchitra Kamle (Providence, RI)
Assignee:
Brown University
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Abstract
Described herein are bispecific antibodies simultaneously targeting both CHI3L1 and the immune checkpoint molecule PD-1. These antibodies manifest enhanced synergistic cytotoxic effects compared to the effects of individual CHI3L1 and PD-1 antibodies, alone or in combination. Methods of treating a cancer by administering the bispecific antibodies described herein are also provided.
Claims (27)
1 . A bispecific antibody that detects and neutralizes chitinase 3-like-1 (CHI3L1) and programmed death receptor 1 (PD-1), wherein the bispecific antibody comprises an antigen-binding portion of an anti-human PD-1 antibody and an antigen-binding portion of an anti-human CHI3L1 antibody, wherein the antigen-binding portion of the anti-human PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 35,
wherein the antigen-binding portion of the anti-human CHI3L1 antibody comprises the complementarity determining regions (CDRs) of:
(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 4;
(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 5;
(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 6;
(d) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 1;
(e) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 2;
(f) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 3, and wherein
1) An anti-human PD-1 single chain variable fragment (ScFv-PD1) is attached to a backbone of the anti-human CHI3L1 antibody, or
2) an anti-human CHI3L1 single chain variable fragment (ScFv-CHI3L1) is attached to a backbone of the anti-human PD-1 antibody.
2 . The bispecific antibody of claim 1 , wherein the ScFv-PD1 is attached to the CHI3L1 antibody heavy chain (CHI3L1-HC-PD1).
3 . The bispecific antibody of claim 1 , wherein the ScFv-PD1 is attached to the CHI3L1 antibody light chain (CHI3L1-LC-PD1).
4 . The bispecific antibody of claim 2 , wherein the CHI3L1 antibody heavy chain has the amino acid sequence of SEQ ID NO: 13.
5 . The bispecific antibody of claim 3 , wherein the CHI3L1 antibody light chain has the amino acid sequence of SEQ ID NO: 14.
6 . The bispecific antibody of claim 1 , wherein the bispecific antibody enhances Jurkat T cell attachment to U87 cells.
7 . The bispecific antibody of claim 6 , wherein the bispecific antibody enhances the ability of Jurkat T cells to induce cytotoxic/apoptotic responses in U87 cells.
8 . The bispecific antibody of claim 6 , wherein the bispecific antibody enhances the accumulation of granzyme and perforin in Jurkat T cells that are in co-culture with U87 cells.
9 . The bispecific antibody of claim 6 , wherein the bispecific antibody enhances the ability of Jurkat T cells to induce lactate dehydrogenase (LDH) release and cell cytotoxicity responses in U87 cells.
10 . A pharmaceutical composition comprising the bispecific antibody of claim 1 and a pharmaceutically acceptable carrier.
11 . The pharmaceutical composition of claim 10 , further comprising a chemotherapeutic agent.
12 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of the bispecific antibody of claim 1 or a pharmaceutical composition of claim 10 .
13 . The method of claim 12 , wherein the cancer is a malignant cancer.
14 . The method of claim 12 , wherein the cancer is a primary cancer or a metastatic cancer.
15 . The method of claim 12 , wherein the cancer is selected from the group consisting of: pancreatic cancer, prostate cancer, colon cancer, rectal cancer, ovarian cancer, kidney cancer, breast cancer, glioblastoma, melanoma, malignant melanoma, and lung cancer.
16 . The method of claim 12 , wherein the subject is determined to have an elevated level of CHI3L1.
17 . The method of claim 16 , wherein the level of CHI3L1 is circulating CHI3L1.
18 . The method of claim 12 , wherein the cancer expresses PD-L1.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 17, 2021
From: ELIAS, JACK A.; LEE, CHUN GEUN; KAMLE, SUCHITRA
To: BROWN UNIVERSITY
Reel/Frame 058139/0738 →
Continuity (4)
Provisional Application
62898324
· Sep 10, 2019
Provisional Application
62876507
· Jul 19, 2019
Provisional Application
62843931
· May 6, 2019
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