According to the Zhitong Finance APP, Hutchmed China (00013) announced that it will present preclinical data for HMPL-A251 at the AACR-NCI-EORTC International Conference on Molecular Targeted and Cancer Therapeutics held in Boston, USA, from October 22 to 26, 2025. HMPL-A251 is a world-first PI3K/AKT/mTOR (PAM)-HER2 antibody-drug conjugate (ATTC), composed of a highly selective and potent PI3K/PIKK inhibitor as the payload and a humanized anti-HER2 IgG1 antibody linked via a cleavable linker.
HER2 is a well-established therapeutic target. HER2 overexpression is commonly found in various tumors and is often associated with poor prognosis. The PAM signaling pathway, as a key downstream signaling pathway of HER2, significantly increases resistance to HER2-targeted therapies when altered. HMPL-A251 is designed to leverage the synergistic effects between HER2-targeted therapy and PAM pathway inhibition, thereby overcoming the limitations of traditional antibody-drug conjugates (ADCs) and single PAM inhibitors.
In in vitro experiments, its PI3K/PIKK inhibitor payload demonstrated strong, high-selectivity, and broad anti-tumor activity across 130 tumor cell lines. The ATTC compound HMPL-A251, formed by conjugating this potent payload with the anti-HER2 antibody via a hydrophilic linker, undergoes rapid endocytosis, lysosomal transport, payload release, and inhibition of PAM and PIKK signaling pathways upon binding to HER2-positive target cells, thereby inducing tumor cell apoptosis. HMPL-A251 exhibited HER2-dependent anti-tumor activity in in vitro models, effectively inhibiting the growth of HER2-positive tumor cells regardless of PAM pathway alterations; however, its activity was slightly reduced in cell lines with low HER2 expression and PAM alterations. When co-cultured with HER2-positive cells, HMPL-A251 also demonstrated a bystander effect on HER2-negative cells.
Traditional cytotoxic ADCs often face toxicity issues related to their cytotoxic payloads. In contrast, the ATTC design emphasizes the precise delivery of payloads with regulatory pathway effects to tumor tissues, enhancing the safety of long-term use and laying the groundwork for potential combination chemotherapy in frontline treatment. In in vivo experiments, HMPL-A251 exhibited superior anti-tumor efficacy and tolerability compared to the combination of naked antibodies and payloads. A single intravenous injection of HMPL-A251 induced tumor regression in various models, including HER2-positive and HER2-low expression models, regardless of PAM alterations. The efficacy was closely related to the concentration of the payload in tumor tissues and the degree of target inhibition. Notably, compared to T-DXd (trastuzumab deruxtecan, a HER2-targeted ADC), HMPL-A251 achieved better or comparable efficacy at equivalent doses in most experimental models. Furthermore, due to the plasma exposure of free payload being far lower than that of HMPL-251, with a quality ratio of less than 1:500,000, the toxicity related to the payload is expected to be low
Dr. Shi Ming, Head of R&amp;D and Chief Medical Officer of HUTCHMED, stated: &#34;HMPL-A251 is the first candidate drug under our ATTC platform, and we are very pleased to share its development progress. It is expected to achieve 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-targeted therapy, HMPL-A251 has demonstrated strong anti-tumor effects while maintaining good safety. The encouraging preclinical data announced highlights its potential to redefine treatment regimens for various cancers. We look forward to advancing HMPL-A251 and more ATTC candidate drugs into clinical trials.&#34;
HUTCHMED plans to initiate global clinical trials for HMPL-A251 by the end of 2025 and submit global new drug clinical trial applications for several other ATTC candidate drugs in 2026.
HUTCHMED's Antibody-Targeted Conjugate (ATTC) platform represents a new generation of precision oncology treatment, achieving a dual mechanism of action by linking monoclonal antibodies with proprietary targeted small molecule inhibitors. Unlike traditional toxin-based ADCs, ATTC demonstrates synergistic anti-tumor activity and durable responses in preclinical models by combining targeted therapy, offering better efficacy and safety compared to the use of antibodies or small molecule inhibitors alone.
Leveraging HUTCHMED's over 20 years of expertise in targeted therapy, this platform has the potential to develop candidate drugs that cover a wide range of tumors. Through antibody-guided targeted delivery and tumor-specific payload release, ATTC can more easily reach tumors and reduce toxicity to non-tumor tissues, thereby overcoming the limitations of small molecule inhibitors, ensuring long-term safety of treatment, and supporting combination therapies with chemotherapy and immunotherapy, making earlier lines of treatment possible

00013

HUTCHMED will present preclinical data for HMPL-A251 at the AACR-NCI-EORTC International Conference in Boston, USA, from October 22 to 26, 2025. HMPL-A251 is a world-first PI3K/AKT/mTOR-HER2 antibody-drug conjugate designed to overcome the limitations of traditional antibody-drug conjugates through synergistic effects. The drug has demonstrated strong and broad anti-tumor activity across 130 tumor cell lines, effectively inhibiting the growth of HER2-positive tumor cells

HUTCHMED announced HMPL-A251 data at the AACR-NCI-EORTC International Conference on Molecular Targeted Therapy and Cancer Treatment