Abstract Background: EGFR is highly expressed in multiple types of solid tumors and well recognized as a driving force in tumorigenesis and disease progression. Modulation of the PI3K/AKT/mTOR (PAM) pathway is required for EGFR-mediated tumorigenesis or conferred resistance to EGFR-targeted therapy. Importantly, PAM pathway inhibition synergizes anti-EGFR therapy to enhance anti-tumor activity. Consequently, an Antibody-Targeted Therapy Conjugate (“ATTC”) with a PI3K/PIKK small molecule inhibitor conjugated to an EGFR antibody is developed and expected to enhance anti-tumor efficacy of anti-EGFR therapy while reducing off-tumor toxicities of PAM inhibitors. HMPL-A580 is a first-in-class ATTC comprising of a highly selective and potent PI3K/PIKK inhibitor payload linked to an anti-EGFR IgG1 antibody, via a cleavable linker. Methods: EGFR binding and internalization were evaluated by FACS. Confocal microscopic imaging was used to monitor endocytosis. Cell viability was measured by CCK-8 or luminescence in 3D cell viability assays. Multiple human xenograft tumors were applied in immune-deficient mice to investigate the anti-tumor activity of HMPL-A580. Results: The payload of HMPL-A580 potently inhibited PI3K and PIKK family kinases, with IC50 ranging around 1 to 10 nM. Eurofins profiling across 418 kinases revealed the payload has excellent selectivity. By conjugating this potent payload with an anti-EGFR antibody via a cleavable linker, the ATTC compound HMPL-A580 demonstrated robust anti-tumor effect. Upon binding to EGFR-expression cancer cell line, HMPL-A580 underwent rapid internalization, lysosomal trafficking, payload release, and PAM and PIKK signaling inhibition to induce tumor cell apoptosis. In a 38-human solid tumor cell line panel, HMPL-A580 potently inhibited EGFR-expression tumor cell proliferation. The tumor cells harboring EGFR high expression, EGFR mut or PAM alterations were more sensitive to HMPL-A580. HMPL-A580 showed a strong bystander effect when EGFR-negative cells co-cultured with EGFR-expression cells. In human tumor xenograft models in mice, HMPL-A580, administered intravenously at 1∼10 mg/kg once weekly for two weeks, demonstrated a dose / exposure-dependent anti-tumor activity in multiple EGFR-expression models, which is associated with much stronger target inhibition and suppression of downstream functions than antibody and payload alone treatment. The preliminary results demonstrated that HMPL-A580 was stable in human, monkey, rat and mouse plasma, and showed favorable PK property in cynomolgus monkeys. Conclusion: HMPL-A580 demonstrates strong anti-tumor activity in preclinical models and good PK characteristics, supporting further clinical evaluation. Citation Format: Yu Cai, Xiangling Chen, Shishuang Chen, Na Yang, Yan Xu, Huijing Yu, Shiming Fan, Haibin Yang, Min Cheng, Nelson Ng, Jianlin He, Shaohui Shen, Weigang He, wei shao, xiaoming dai, Yajing Bai, Yizhen Yang, linfang wang, Jian Wang, Weihan Zhang, Yongxin Ren, Guangxiu Dai, Michael Shi, Weiguo Su. Discovery of HMPL-A580, a first-in-class antibody-targeted therapy conjugate (ATTC) of a novel PI3K/PIKK inhibitor payload linked to an anti-EGFR antibody abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4549.
Cai et al. (Fri,) studied this question.