HUTCHMED announced promising preclinical data for HMPL-A251, a first-in-class PI3K/AKT/mTOR-HER2 Antibody-Targeted Therapy Conjugate (ATTC), at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics held October 22-26, 2025, in Boston. The novel therapeutic represents the first investigational drug candidate from HUTCHMED's innovative ATTC technology platform, designed to overcome limitations of traditional toxin-based antibody-drug conjugates.
Novel Mechanism Targets HER2 and PAM Pathway Synergy
HMPL-A251 comprises a highly selective and potent PI3K/PIKK inhibitor payload linked to a humanized anti-HER2 IgG1 antibody via a cleavable linker. The compound leverages the synergy between HER2 targeting and PAM pathway inhibition to address resistance mechanisms that limit current HER2-targeting treatments.
HER2 overexpression occurs across various cancer types and correlates with poor prognosis. The PAM pathway, a key downstream signaling cascade of HER2, contributes significantly to treatment resistance when altered. HMPL-A251's innovative design specifically targets this vulnerability by combining precise HER2 targeting with selective pathway modulation.
Robust Preclinical Efficacy Across Multiple Models
In vitro studies demonstrated the PI3K/PIKK inhibitor payload exhibited high potency, selectivity, and broad anti-tumor activity across a panel of 130 tumor cell lines. Upon binding to HER2-positive target cells, HMPL-A251 undergoes rapid internalization, lysosomal trafficking, and payload release, leading to inhibition of PAM and PIKK signaling and subsequent tumor cell apoptosis.
The compound demonstrated HER2-dependent antitumor activity, potently inhibiting HER2-positive tumor cell growth regardless of PAM pathway alterations. Activity was moderately reduced in HER2-low, PAM-altered cell lines. Notably, HMPL-A251 also exhibited a bystander effect on HER2-null cells when co-cultured with HER2-positive cells.
Superior In Vivo Performance and Safety Profile
In vivo studies revealed HMPL-A251 demonstrated superior anti-tumor efficacy and tolerability compared to the naked antibody and payload administered together. A single intravenous dose induced tumor regression across multiple models, including HER2-positive and HER2-low models with or without PAM alteration. Efficacy correlated strongly with payload concentration and target inhibition in tumor tissue.
When benchmarked against trastuzumab deruxtecan (T-DXd), a HER2-directed ADC, HMPL-A251 achieved superior or comparable efficacy at equivalent doses in most tested models. The safety profile appears favorable, with plasma exposure of free payload significantly lower than HMPL-251, maintaining a mass ratio of less than 1:500,000.
ATTC Platform Addresses ADC Limitations
Unlike traditional cytotoxin-based ADCs that face toxicity challenges related to their cytotoxic payloads, ATTCs prioritize tumor-specific delivery of pathway-modulating payloads. This approach enhances safety for long-term use and enables potential frontline combinations with chemotherapy.
"We are excited to share the progress of HMPL-A251, the first candidate from our ATTC platform. It represents a potentially significant leap forward in addressing the limitations of toxin-based ADCs and narrow therapeutic window of systemic PAM inhibitors," said Dr. Michael Shi, Head of R&D and Chief Medical Officer of HUTCHMED. "By combining selective PI3K/PIKK inhibition with precise HER2 targeting, HMPL-A251 achieves potent antitumor effects while maintaining a favorable safety profile."
Clinical Development Timeline
HUTCHMED plans to initiate global clinical trials for HMPL-A251 around the end of 2025. The company expects to file multiple global Investigational New Drug applications for additional ATTC candidates in 2026, expanding the platform's clinical footprint.
The ATTC platform builds on over 20 years of targeted therapy expertise, enabling development of drug candidates for diverse cancer types. By leveraging antibody-guided delivery and tumor-specific payload release, ATTCs improve tumor accessibility while reducing off-tumor toxicity, supporting combinations with chemotherapy and immunotherapy for potential early-line treatments.
