Abstract C086: First-in-class PI3Kα-targeting degrader antibody conjugates (DACs) for selective and safer treatment of PI3Kα-driven cancers

Abstract PI3Kα is a critical oncogenic driver in a broad range of solid tumors, including breast cancer, where activating mutations and pathway hyperactivation are frequently observed. Although two PI3Kα inhibitors have recently been approved by the FDA for breast cancer treatment, their clinical utility is significantly constrained by dose-limiting, on-target toxicities due to wild-type PI3Kα inhibition, most notably insulin resistance and hyperglycemia. Antibody-drug conjugates (ADCs) offer a compelling strategy to enhance the therapeutic index of PI3Kα-targeted therapies. However, development of such agents has been hindered by the lack of sufficiently potent and selective PI3Kα inhibitors suitable as ADC payloads. To address this, we utilized Accutar’s proprietary chimeric degrader platform to develop AC4847, a highly potent and selective PI3Kα degrader. By recruiting the Cereblon E3 ligase, AC4847 induced rapid, dose-dependent degradation of PI3Kα and suppression of downstream pAKT signaling across cell lines harboring diverse PI3Kα mutation statuses. AC4847 exhibited sub-nanomolar potency, approximately 100-fold more potent than the small-molecule PI3Kα inhibitor inavolisib, with minimal activity against other PI3K isoforms or Cereblon-associated neosubstrates. When conjugated to TROP2 or HER2 antibodies, AC4847-based degrader-antibody conjugates (DACs) elicited antigen-dependent PI3Kα degradation and robust anti-proliferative effects, with enhanced potency in cell lines expressing high levels of target antigen. In HER2-overexpressing BT-474 and JIMT-1 breast cancer xenograft models, a single dose of trastuzumab-conjugated PI3Kα DAC at 5 mg/kg or lower (administered once every three weeks) achieved durable tumor regression, accompanied by effective PI3Kα degradation and pAKT suppression. Notably, under equivalent plasma DAC exposures, no significant changes in blood glucose or insulin levels were observed in mice, rats, or non-human primates, contrasting with the pronounced metabolic toxicity seen with inavolisib at efficacious exposures. In conclusion, these preclinical studies demonstrated that PI3Kα-targeted DACs using degrader AC4847 delivered potent, antigen-dependent anti-tumor efficacy while significantly reducing systemic toxicity compared to traditional small-molecule PI3Kα inhibitors. By leveraging the mechanistic advantages of chimeric degraders, such as catalytic target elimination, sustained pathway suppression dependent on protein resynthesis, and the ability to eliminate non-enzymatic scaffold functions, AC4847 offers a novel mode of action that enhances selectivity and durability of response. These attributes, combined with the targeted delivery enabled by antibody conjugation, support the advancement of AC4847-derived DACs into IND-enabling studies as a first-in-class therapeutic strategy for PI3Kα-driven cancers. Citation Format: Wei He1, Pin Huang1, Yan Feng1, Jie Su1, Hiep Tran1, Matthew Gregory1, Nathan Slotnick1, Robert Luo1, Ji Liu1, Jie Fan1. First-in-class PI3Kα-targeting degrader antibody conjugates (DACs) for selective and safer treatment of PI3Kα-driven cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C086.