IP Library › Granted Patent US 12,630,632
Granted Patent B2
US 12,630,632 · App. 17/355,756 · Granted May 19, 2026

Bispecific HER2 and CD3 binding molecules

Inventors: Nai-Kong V. Cheung (New York, NY); Andres Lopez-Albaitero (New York, NY); Hong Xu (New York, NY)
Assignee: Memorial Sloan Kettering Cancer Center
C07K16/2809A61P35/04C07K16/32A61K39/3955A61K39/39566A61K2039/505C07K2317/31C07K2317/52C07K2317/56C07K2317/622C07K2317/64C07K2317/73C07K2317/92C07K2319/33
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Quick Facts
Patent No.
US 12,630,632
App. No.
17/355,756
Granted
May 19, 2026
Kind
B2
Abstract

Provided herein are compositions, methods, and uses involving bispecific binding molecules that specifically bind to HER2, a receptor tyrosine kinase, and to CD3, a T cell receptor, and mediate T cell cytotoxicity for managing and treating disorders, such as cancer. Also provided herein are uses and methods for managing and treating HER2-related cancers.

Claims (30)

1 . A method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific binding molecule comprising an aglycosylated monoclonal antibody that is an immunoglobulin that binds to HER2, said immunoglobulin comprising two identical heavy chains and two identical light chains, said light chains being a first light chain and a second light chain, wherein the first light chain is fused to a first single chain variable fragment (scFv), via a peptide linker, to create a first light chain fusion polypeptide, and wherein the second light chain is fused to a second scFv, via a peptide linker, to create a second light chain fusion polypeptide, wherein the first and second scFv (i) are identical, and (ii) bind to CD3, and wherein the first and second light chain fusion polypeptides are identical;

wherein the level of HER2 in the cancer is characterized as IHC 2+, or IHC 1+, wherein the cancer is resistant to trastuzumab, and wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, an osteosarcoma, desmoplastic small round cell cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioblastoma multiforme, gastric junction adenocarcinoma, gastroesophageal junction adenocarcinoma, cervical cancer, salivary gland cancer, soft tissue sarcoma, leukemia, melanoma, Ewing's sarcoma, rhabdomyosarcoma, and neuroblastoma,

wherein the heavy chains comprise a V H domain present in any of SEQ ID NOs: 23, 27, 62 or 63;

wherein the light chains comprise a V L domain present in SEQ ID NO: 25; and

wherein the first and second scFvs comprise a VH domain having a sequence selected from the group consisting of SEQ ID NOs: 15, 17 and 64, and a V L domain having a sequence selected from the group consisting of SEQ ID NOs: 16 and 65; and

wherein the cancer is resistant to PDL1 blockade with an anti-PDL1 antibody therapy or PD1 blockade with an anti-PD1 antibody therapy.

2 . The method of claim 1 , wherein the cancer expresses HER2 levels that are lower relative to cancers that are indicated for treatment with trastuzumab and are of the same tissue type as the cancer.

3 . The method of claim 1 , wherein

(a) the level of HER2 in the cancer is characterized as IHC 1+ when the test specimen exhibits an incomplete HER2 membrane staining that is faint/barely perceptible and within greater than 10% of the invasive tumor cells, wherein the staining is readily appreciated using a low-power objective;

(b) the level of HER2 in the cancer is characterized as IHC 2+ when the test specimen exhibits (1) a circumferential HER2 membrane staining that is incomplete and/or weak/moderate and within greater than 10% of invasive tumor cells, wherein the staining is observed in a homogenous and contiguous population, and wherein the staining is readily appreciated using a low-power objective; or (2) a complete and circumferential HER2 membrane staining that is intense and within less than or equal to 10% of invasive tumor cells, wherein the staining is readily appreciated using a low-power objective.

4 . The method of claim 1 , wherein:

(I) the level of HER2 in the cancer is characterized as IHC 2+ when the test specimen exhibits (1) a circumferential HER2 membrane staining that is incomplete and/or weak/moderate and within greater than 10% of invasive tumor cells, wherein the staining is observed in a homogenous and contiguous population, and wherein the staining is readily appreciated using a low-power objective; or (2) a complete and circumferential HER2 membrane staining that is intense and within less than or equal to 10% of invasive tumor cells, wherein the staining is readily appreciated using a low-power objective; or

(II) the level of HER2 in the cancer is characterized as IHC 1+ when the test specimen exhibits an incomplete HER2 membrane staining that is faint/barely perceptible and within greater than 10% of the invasive tumor cells, wherein the staining is readily appreciated using a low-power objective.

5 . The method of claim 1 , wherein the cancer is a programmed death-ligand 1 (PDL1)-positive cancer.

6 . The method of claim 5 , wherein the cancer overexpresses PDL1 relative to expression of PDL1 in analogous noncancerous cells of the same tissue type as the cancer.

7 . The method of claim 1 , wherein the anti-PDL1 antibody therapy comprises atezolizumab or wherein the anti-PD1 antibody therapy comprises pembrolizumab.

8 . The method of claim 1 , wherein:

(a) the sequence of each heavy chain is any of SEQ ID NOs: 27 or 62; or

(b) the sequence of each light chain is SEQ ID NO: 25; or

(c) the sequence of the peptide linker is any of SEQ ID NOs: 14 or 35-41; or

(d) the sequence of an intra-scFv peptide linker between the V H domain and the V L domain in the first scFv is any of SEQ ID NOs: 14 or 35-41; or

(e) the sequence of the scFv is any of SEQ ID NOs: 19 or 48-59; or

(f) the sequence of the first light chain fusion polypeptide is any of SEQ ID NOs: 29, 34, 42-47, or 60.

9 . The method of claim 1 , wherein

the sequence of each heavy chain is SEQ ID NO: 27, and wherein the sequence of each light chain is SEQ ID NO: 25;

the sequence of each heavy chain is SEQ ID NO: 62 and wherein the sequence of each light chain fusion polypeptide is SEQ ID NO: 60;

the sequence of each heavy chain is SEQ ID NO: 27 and wherein the sequence of each light chain fusion polypeptide is SEQ ID NO: 34;

the sequence of each heavy chain is SEQ ID NO: 27 and wherein the sequence of each light chain fusion polypeptide is SEQ ID NO: 47; or

the sequence of each heavy chain is SEQ ID NO: 27 and wherein the sequence of each light chain fusion polypeptide is SEQ ID NO: 29.

10 . The method of claim 1 , wherein the cancer is resistant to treatment with cetuximab, lapatinib, erlotinib, or any other small molecule or antibody that targets the HER family of receptors.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 3, 2023
From: CHEUNG, NAI-KONG V.; LOPEZ-ALBAITERO, ANDRES; XU, HONG
To: MEMORIAL SLOAN KETTERING CANCER CENTER
Reel/Frame 063207/0024 →
Continuity (3)
Continuation 15881042 · Jan 26, 2018
Provisional Application 62451155 · Jan 27, 2017
Related Publication 20210324079A1 · Oct 21, 2021
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