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Broad-Spectrum Efficacy of CEACAM6-Targeted Antibody-Drug Conjugate with BET Protein Degrader in Colorectal, Lung,
Hiroyuki Kogai1, Shuntaro Tsukamoto1, Minaho Koga1
1Tsukuba Research Laboratory, Eisai Co., Ltd., Ibaraki, Japan.
Abstract:
Despite remarkable advances in cancer treatment, most solid cancers remain difficult to cure. We recently developed an antibody-drug conjugate (ADC; 84-EBET) for pancreatic cancer by using the carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) antibody #84.7 and the bromodomain and extra-terminal (BET) protein degrader EBET. In this study, we showed the overexpression of CEACAM6 in colorectal, lung, and breast cancers and the broad-spectrum efficacy of 84-EBET in mouse models of these cancers. In vitro assays using cancer organoids and cell lines of colorectal, lung, and breast cancers revealed that 84-EBET was more potent than ADCs with known approved payloads-DXd, SN38, and monomethyl auristatin E-or standard chemotherapies. In mouse studies, a single injection of 84-EBET induced marked regression of colorectal-, lung-, and breast cancer patient-derived xenograft tumors and cell line-derived xenograft tumors. Moreover, in mouse syngeneic colorectal cancer, lung cancer, and breast cancer models resistant to PD-1 antibody, the combination of 84-EBET and PD-1 antibody induced complete regression of most tumors. Mechanistically, 84-EBET degraded bromodomain-containing protein 4 in both cancer and stromal cells via bystander efficacy. It decreased stromal inflammatory phenotypes and increased activated T-cell numbers in tumors. These results demonstrate that delivering BET protein degraders to tumors and their microenvironments via a CEACAM6-targeted ADC may be effective against a wide range of solid cancers.
Insights
A novel antibody-drug conjugate, 84-EBET, targets carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) to degrade bromodomain and extra-terminal (BET) proteins. This new cancer therapy shows broad efficacy across multiple solid tumors, including colorectal, lung, and breast cancers.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Solid cancers like colorectal, lung, and breast cancers remain challenging to treat despite advances.
- Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is overexpressed in various solid tumors.
- Antibody-drug conjugates (ADCs) offer targeted cancer therapy by delivering cytotoxic payloads.
Purpose of the Study:
- To evaluate the efficacy of a novel ADC, 84-EBET, targeting CEACAM6 and delivering a bromodomain and extra-terminal (BET) protein degrader.
- To assess the anti-tumor activity of 84-EBET across diverse solid cancer models, including those resistant to immunotherapy.
- To elucidate the mechanism of action of 84-EBET, including its effects on tumor microenvironment and immune cells.
Main Methods:
- Development of 84-EBET using a CEACAM6-specific antibody and a BET protein degrader.
- In vitro testing using cancer organoids and cell lines from colorectal, lung, and breast cancers.
- In vivo studies using patient-derived xenografts (PDX) and syngeneic models of colorectal, lung, and breast cancers.
- Combination therapy studies with PD-1 antibody in immunotherapy-resistant models.
Main Results:
- 84-EBET demonstrated broad-spectrum efficacy in mouse models of colorectal, lung, and breast cancers.
- In vitro, 84-EBET outperformed ADCs with established payloads (e.g., DXd, SN38) and standard chemotherapies.
- A single 84-EBET injection induced significant tumor regression in xenograft models.
- Combination of 84-EBET and PD-1 antibody led to complete tumor regression in resistant syngeneic models.
- 84-EBET degraded BET proteins in cancer and stromal cells, reduced inflammation, and increased T-cell infiltration.
Conclusions:
- CEACAM6-targeted delivery of BET protein degraders via ADCs represents a promising strategy for treating a wide range of solid cancers.
- 84-EBET exhibits potent anti-tumor activity and overcomes resistance to PD-1 immunotherapy.
- The mechanism involves direct tumor cell killing and modulation of the tumor microenvironment, enhancing anti-tumor immunity.
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