Akeso Unveils MOA for CLDN18.2/CD47 Bispecific Antibody AK132 at SITC Meeting

HONG KONG, Nov. 7, 2024 – During the 2024 Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2024) in Houston, Akeso Biopharma (9926.HK) shared significant research findings on its innovative bispecific antibody, AK132. This antibody targets Claudin18.2 (CLDN18.2) and CD47, showcasing its potential in cancer treatment.

AK132 is a bispecific antibody with a unique "1+1" valency that targets and blocks both CLDN18.2 and CD47. It incorporates a wild-type IgG1 Fc structure, and is currently undergoing clinical research.

CD47 is found in high levels on various cancer cells and interacts with SIRPα on immune cells, hindering tumor phagocytosis. Claudin18.2 (CLDN18.2), a protein involved in cell junctions, is overexpressed in several primary cancers and is considered a significant target in gastric and pancreatic cancers.

Research indicates that AK132 binds tightly to human CLDN18.2 and CD47. It blocks the interaction between CD47 and SIRPα, which disrupts the CD47-SIRPα axis. This process frees tumor cells from inhibition and allows macrophages to phagocytize CLDN18.2+/CD47+ tumor cells, thereby boosting immune responses against tumors. Additionally, AK132 induces robust tumor cell death through Fc-mediated processes like ADCC, ADCP, and CDC, showing better efficacy than anti-CLDN18.2 monoclonal antibodies in mouse tumor models.

Studies have shown that AK132 binds with high specificity to CLDN18.2 and CD47, stopping the CD47-SIRPα interaction. This mechanism enhances immune cell functionality in eliminating tumors. AK132 facilitates macrophage phagocytosis of dual-positive tumor cells and inhibits tumor growth in mouse xenograft models. Moreover, it kills tumor cells efficiently via Fc-mediated actions, including ADCC, ADCP, and CDC.

One significant advantage of AK132 is its lack of toxicity to red blood cells. Although CD47 is a target for cancer immunotherapy, CD47 monoclonal antibodies often harm red blood cells. AK132’s design minimizes its affinity for CD47 on red blood cells, thus avoiding ADCP and ADCC activities against them and preventing red blood cell aggregation. This design ensures good safety profiles without causing red blood cell damage.

Akeso’s investigational New Drug (IND) application for AK132, which aims to treat advanced solid tumors, has received approval from China’s National Medical Products Administration (NMPA). Akeso has developed a comprehensive pipeline of bispecific antibodies, creating a competitive edge in cancer immunotherapy. The company’s market-approved antibodies include cadonilimab (PD-1/CTLA-4 bispecific) and ivonescimab (PD-1/VEGF bispecific). Additionally, four other bispecific antibodies, namely AK129 (PD-1/LAG-3), AK130 (TIGIT/TGF-β fusion protein), AK131 (PD-1/CD73), and AK132, are in clinical trials.

AK132 targets Claudin18.2 and CD47 splice variant 2, aiming to treat various cancers, including gastric, esophageal, pancreatic, ovarian, and lung adenocarcinomas. It binds effectively to human CLDN18.2 and CD47, interrupting CD47-SIRPα interactions. In mouse models, AK132 significantly curbs tumor growth. It exhibits no ADCC or ADCP activity against human red blood cells and does not cause their aggregation, suggesting it is both effective and safe as a cancer therapy.

Akeso, founded in 2012, is a prominent biopharmaceutical company focused on developing innovative biological drugs. The company has a comprehensive R&D platform and a robust manufacturing system. Akeso has an extensive pipeline of over 50 innovative drugs targeting cancer, autoimmune diseases, inflammation, and metabolic disorders. With 22 candidates in clinical trials and several drugs commercially available, Akeso is committed to providing affordable therapeutic antibodies and emerging as a global leader in biopharmaceuticals.