HUTCHMED (00013) announced the presentation of preclinical data for HMPL-A251 at the AACR-NCI-EORTC Molecular Targeted Therapy and Cancer Treatment International Conference, held from October 22 to 26, 2025, in Boston, USA. HMPL-A251 is a first-in-class PI3K/AKT/mTOR (PAM)-HER2 antibody-drug conjugate (ATTC), combining a highly selective, potent PI3K/PIKK inhibitor as the payload and a fully humanized anti-HER2 IgG1 antibody through a cleavable linker. HER2 is an established therapeutic target, commonly overexpressed in various tumors and associated with poor prognosis. The PAM signaling pathway is a crucial downstream pathway of HER2; alterations in this pathway significantly increase resistance to HER2-targeted therapies. HMPL-A251 is designed to synergistically leverage HER2 targeting with PAM pathway inhibition, aiming to overcome the limitations of conventional cytotoxic antibody-drug conjugates (ADCs) and single PAM inhibitors. In vitro studies demonstrated that its PI3K/PIKK inhibitor payload exhibited strong, selective, and broad antitumor activity across 130 tumor cell lines. The ATTC compound, HMPL-A251, created by conjugating this potent payload with the anti-HER2 antibody via a hydrophilic linker, rapidly undergoes endocytosis, lysosomal transport, payload release, and inhibition of PAM and PIKK signaling upon binding to HER2-positive target cells, thereby inducing tumor cell apoptosis. HMPL-A251 showed HER2-dependent antitumor activity in vitro, effectively inhibiting growth in HER2-positive tumor cells regardless of PAM pathway alterations; however, its activity was somewhat reduced in HER2 low-expressing cell lines with PAM changes. Notably, when co-cultured with HER2-positive cells, HMPL-A251 exhibited a bystander effect on HER2 non-expressing cells. Traditional cytotoxic ADCs often face toxicity issues related to their cytotoxic payloads. In contrast, the ATTC design emphasizes the precise delivery of regulators to tumor tissues, enhancing long-term safety of administration and laying the groundwork for its potential frontline combination chemotherapy applications. In vivo experiments demonstrated that HMPL-A251 exhibited superior antitumor efficacy and tolerability compared to combinations of naked antibodies and payloads. A single intravenous dose of HMPL-A251 induced tumor regression in various models, including both HER2-positive and HER2 low-expressing models, irrespective of PAM alterations. Efficacy was closely associated with the concentration of the payload and the degree of target inhibition in tumor tissues. Importantly, compared to T-DXd (trastuzumab deruxtecan, a HER2-targeting ADC), HMPL-A251 achieved better or comparable efficacy at equivalent doses in most test models. Additionally, due to significantly lower plasma exposure of the free payload compared to HMPL-251 dosage, with a ratio of less than 1:500,000, lower toxicity related to the payload is anticipated. Dr. Ming Shi, Head of R&D and Chief Medical Officer at HUTCHMED, stated, “HMPL-A251 is our first candidate from the ATTC platform, and we are excited to share its development progress. It holds promise for significant breakthroughs in overcoming the limitations of toxin-based ADCs and the narrow therapeutic window of systemic PAM inhibitors. By combining selective PI3K/PIKK inhibition with precise HER2 targeting, HMPL-A251 demonstrates potent antitumor effects while maintaining favorable safety. The encouraging preclinical data released highlights its potential to redefine treatment paradigms for various cancers. We look forward to advancing HMPL-A251 along with more ATTC candidates into clinical trials.” HUTCHMED plans to initiate global clinical trials for HMPL-A251 by the end of 2025 and to submit global new drug clinical trial applications for several other ATTC candidates in 2026. HUTCHMED's antibody-drug conjugate (ATTC) platform represents a new generation of precision oncology treatment, combining monoclonal antibodies with proprietary targeted small molecule inhibitor payloads for dual action mechanisms. Unlike traditional cytotoxic ADCs, ATTC exhibits synergistic antitumor activity and prolonged responses in preclinical models, showing better efficacy and safety compared to using antibodies or small molecule inhibitors alone. Leveraging over twenty years of expertise in targeted therapies, this platform has the potential to develop candidates that cover a broad range of tumors. Through antibody-guided targeted delivery and tumor-specific payload release, ATTC facilitates easier access to tumors while reducing toxicity to non-tumor tissues, thereby overcoming the limitations of small molecule inhibitors, ensuring long-term safety, and supporting combination therapies with chemotherapy and immunotherapy for earlier-line applications.