Abstract 833: A novel anti-CEACAM6 heavy-chain antibody-drug conjugate for gastrointestinal cancer therapy

Abstract Antibody-drug conjugates (ADCs) are "biological missiles" that utilize a chemical linker to connect monoclonal antibodies (mAbs) with cytotoxic drugs, which induces the precise killing of targeted tumor cells and causes the death of surrounding untargeted cancer cells through the bystander effect. However, current ADCs are too specific to certain cancer subtypes and not specific enough to accurately target a cancer-specific protein, which limits the therapeutic populations and induces unwanted side effects. We developed a heavy-chain antibody (HCAb) from a llama immune library, which recognizes glycosylated CEACAM6 (Carcinoembryonic antigen-related cell adhesion molecule 6), a broad-surface marker of epithelial-type cancers. The anti-CEACAM6 HCAb showed a higher affinity (KD: sub-nanomolar), better thermal stability, unique tissue penetration and epitope-recognition abilities compared to the conventional antibodies. The anti-CEACAM6 HCAb-drug conjugate (HCAb-ADC), which links the HCAb and tubulin inhibitors via hydrophilic linkers, specifically killed CEACAM6-expressing colorectal (CRC), lung, pancreas, and bile duct carcinoma cells at sub-nanomolar concentrations and had a better anti-cancer effect than current FDA-approved ADCs. In xenograft models, a single administration of HCAb-ADC completely abolished colorectal and pancreatic tumors. Notably, HCAb-ADC can effectively inhibit tumor growth even at very low doses (0.2 mg/Kg) and demonstrated a superior therapeutic effect over current therapeutic regimens. Meanwhile, it exhibited minimal toxicity to normal epithelial and peripheral blood mononuclear cells. In summary, the excellent anti-tumor activity across different epithelial cancers and minimal toxicity to normal tissues support the clinical development of the novel HCAb-ADC for treating multiple epithelial-type cancers, including CRC, lung, pancreatic, and bile duct carcinoma. Citation Format: Ming-Heng Wu, Yao-Tsung Tsai, Chee Voon Yap. A novel anti-CEACAM6 heavy-chain antibody-drug conjugate for gastrointestinal cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 833.