On November 7, 2024 Akeso Biopharma (9926. HK) reported the mechanism of action (MOA) research findings of its innovative bispecific antibody, AK132, targeting both Claudin18.2 (CLDN18.2) and CD47 at the 2024 Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (SITC 2024), held in Houston, USA, from November 6 – 10 (Press release, Akeso Biopharma, NOV 7, 2024, View Source [SID1234647978]). AK132 is an asymmetric bispecific antibody with a "1+1" valency, designed to simultaneously target and block CLDN18.2 and CD47. It features a wild-type IgG1 Fc structure and is currently in the clinical research stage.

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CD47 is overexpressed on a variety of cancer cells, where it interacts with its ligand SIRPα on innate immune cells to inhibit tumor phagocytosis. Claudin 18.2 (CLDN18.2), a tight junction protein, is abnormally activated and overexpressed in several primary malignancies. It has been recognized as a key tumor antigen target in gastric and pancreatic cancers.

Studies have demonstrated that AK132 binds with high affinity to both human CLDN18.2 and human CD47. On one hand, it competitively blocks the interaction between CD47 and its ligand SIRPα, thereby disrupting the CD47-SIRPα axis and relieving the inhibition of tumor cell phagocytosis. This enables macrophage-mediated phagocytosis of CLDN18.2+/CD47+ tumor cells, thereby enhancing the antitumor activity of immune cells. On the other hand, AK132 also induces potent tumor cell killing through Fc-mediated effector functions, such as ADCC, ADCP, and CDC, leading to superior antitumor efficacy compared to anti-CLDN18.2 monoclonal antibodies. In subcutaneous tumor xenograft models in mice, AK132 demonstrated significantly stronger antitumor activity than anti-CLDN18.2 monoclonal antibodies.

Ak132 Efficiently Binds to CLDN18.2 and CD47, Exerting Antitumor Effects through Multiple Mechanisms
Research shows that AK132 binds with high affinity and specificity to human CLDN18.2 and human CD47, competitively blocking the interaction between CD47 and its ligand SIRPα. This disruption of the CD47-SIRPα interaction releases the inhibition on tumor cell phagocytosis, enhancing immune cell anti-tumor functions. AK132 mediates macrophage phagocytosis of CLDN18.2+/CD47+ tumor cells and effectively inhibits tumor growth in subcutaneous xenograft mouse models. AK132 also efficiently kills tumor cells through Fc-mediated effector functions, such as ADCC (antibody-dependent cell-mediated cytotoxicity), ADCP (antibody-dependent cellular phagocytosis), and CDC (complement-dependent cytotoxicity).

AK132 Shows no RBC Toxicity, Does not Bind to Red Blood Cells or Induce Agglutination, Demonstrating Good Safety Profiles
Although CD47 is considered a promising target for cancer immunotherapy, the therapeutic efficacy of CD47 monoclonal antibodies is significantly limited by their considerable toxicity to red blood cells. AK132 features a unique structural design that reduces its affinity for CD47. In vitro studies have shown that AK132 binds minimally to human red blood cells, does not induce ADCP or ADCC activity against red blood cells (thus preventing red blood cell killing), and does not cause red blood cell aggregation, demonstrating an absence of erythrocyte toxicity.

Six Globally Leading Bispecific Antibodies Efficiently Propel Cancer Immunotherapy into the 2.0 Era
Akeso’s investigational New Drug application (IND) application for AK132, aimed at treating advanced malignant solid tumors, has been approved by the China NMPA. Akeso has strategically built a leading, target-rich pipeline of bispecific antibodies, establishing a competitive edge in cancer immunotherapy. Among these, cadonilimab (PD-1/CTLA-4 bispecific) and ivonescimab (PD-1/VEGF bispecific) are already market-approved. Four other bispecific antibodies, including AK129 (PD-1/LAG-3), AK130 (TIGIT/TGF-β fusion protein), AK131 (PD-1/CD73), and AK132 (CLDN18.2/CD47), are currently in clinical trials.