HUTCHMED (00013) announced HMPL-A251 data at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapy.

HUTCHMED (00013) announced that it will present preclinical data of HMPL-A251 at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference in Boston, USA, from October 22 to 26, 2025. HMPL-A251 is a globally pioneering PI3K/AKT/mTOR (PAM)-HER2 antibody-drug conjugate (ATTC) targeting drug, consisting of a highly selective and potent PI3K/PIKK inhibitor as the payload and a humanized anti-HER2 IgG1 antibody linked by a cleavable linker. HER2 is a mature therapeutic target commonly overexpressed in various tumors and often associated with poor prognosis. The PAM signaling pathway, as a key downstream signaling pathway of HER2, significantly increases resistance to HER2-targeted therapies once altered. HMPL-A251, through innovative design, aims to leverage the synergy between HER2-targeted therapy and PAM pathway inhibition, thereby overcoming the limitations of traditional cytotoxic antibody-drug conjugates (ADCs) and single PAM inhibitors. In in vitro experiments, its PI3K/PIKK inhibitor payload demonstrates potent, highly selective, and broad anti-tumor activity in 130 tumor cell lines. The ATTC compound, HMPL-A251, formed by conjugating this potent payload with an anti-HER2 antibody through a hydrophilic linker, induces rapid internalization, lysosomal trafficking, payload release, and inhibition of the PAM and PIKK signaling pathways upon binding to HER2-positive target cells, thereby inducing tumor cell apoptosis. HMPL-A251 demonstrates HER2-dependent anti-tumor activity in in vitro models, effectively inhibiting the growth of HER2-positive tumor cells regardless of PAM pathway alterations, while its activity is slightly reduced in cell lines with low HER2 expression and PAM changes. When co-cultured with HER2-positive cells, HMPL-A251 also exhibits bystander effects on HER2-negative cells. Traditional cytotoxic ADCs often face toxicity issues associated with their cytotoxic payloads. In contrast, the design of ATTC emphasizes the precise delivery of efficacious payloads with pathway-modulating effects to tumor tissues to improve the long-term safety of drug administration and lay the foundation for potential combination therapy in frontline treatment. In in vivo experiments, HMPL-A251 demonstrates superior anti-tumor efficacy and tolerability compared to naked antibodies and combined administration of payload in animal models. Single intravenous injection of HMPL-A251 induces tumor regression in various models, including HER2-positive and HER2 low-expression models, with or without PAM alterations. Efficacy is closely related to the payload concentration and target inhibition degree in tumor tissues. Notably, compared to T-DXd (trastuzumab deruxtecan, a HER2-targeting ADC), HMPL-A251 achieves better or equivalent efficacy at equipotent doses in most experimental models. Furthermore, due to the significantly lower plasma exposure of free payload compared to HMPL-251 doses, with a mass ratio of less than 1:500,000, payload-related toxicity is expected to be low. Dr. Ming Shi, Chief Medical Officer and Head of Research and Development at HUTCHMED, stated, "HMPL-A251 is our first candidate drug under the ATTC platform, and we are excited to share its research progress. It holds promise in overcoming the limitations of toxin-based ADCs and the narrow treatment window of systemic PAM inhibitors. By combining selective PI3K/PIKK inhibition with precise HER2-targeted therapy, HMPL-A251 achieves potent anti-tumor effects while maintaining good safety. The encouraging preclinical data announced highlight its potential to redefine multiple cancer treatment strategies. We look forward to advancing HMPL-A251 and other ATTC candidate drugs into clinical trials." HUTCHMED plans to initiate global clinical trials for HMPL-A251 by the end of 2025 and submit global new drug clinical trial applications for multiple other ATTC candidate drugs in 2026. HUTCHMED's Antibody-Drug Conjugate (ATTC) platform represents a new generation of precision oncology treatment, combining monoclonal antibodies with patented targeted small molecule inhibitor payloads to achieve a dual-action mechanism. Unlike traditional cytotoxic ADCs, ATTC demonstrates synergistic anti-tumor activity and sustained remission in preclinical models by combining targeted therapy, showing better efficacy and safety compared to using antibodies or small molecule inhibitors alone. Leveraging over twenty years of expertise in targeted therapy, HUTCHMED's platform has the potential to develop candidate drugs covering a wide range of tumors. By antibody-guided targeted delivery and tumor-specific payload release, ATTC can more easily reach tumors and reduce toxicity to non-tumor tissues, overcoming the limitations of small molecule inhibitors, ensuring long-term safety of drug administration, and supporting combination therapy with chemotherapy and immunotherapy, making it possible to be used in earlier treatment lines.