HUTCHMED Highlights HMPL-A251 Data Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
HUTCHMED (Nasdaq/AIM: HCM) presented preclinical data for HMPL-A251 at the AACR-NCI-EORTC conference (Oct 22–26, 2025). HMPL-A251 is an ATTC combining a humanized anti-HER2 IgG1 with a highly potent, selective PI3K/PIKK inhibitor payload via a cleavable hydrophilic linker. In vitro it showed broad activity across 130 tumor cell lines, HER2-dependent killing and a bystander effect. In vivo a single IV dose induced tumor regression across HER2-positive and HER2-low models, with efficacy comparable or superior to T-DXd in most models. Free payload plasma exposure was very low (mass ratio <1:500,000). Global clinical trials are planned around end of 2025 with additional IND filings in 2026.
HUTCHMED (Nasdaq/AIM: HCM) ha presentato dati preclinici per HMPL-A251 alla conferenza AACR-NCI-EORTC (22–26 ottobre 2025). HMPL-A251 è un ATTC che combina un anticorpo IgG1 anti-HER2 umanizzato con un carico inibitore PI3K/PIKK altamente potente e selettivo tramite un linker idrofilo cleavable. In vitro ha mostrato una ampia attività su 130 linee cellulari tumorali, una cytotorre HER2-dipendente e un effetto bystander. In vivo, una singola dose endovenosa ha indotto la regressione tumorale in modelli HER2-positivi e HER2-bassi, con efficacia comparabile o superiore a T-DXd nella maggior parte dei modelli. L'esposizione plasmatica del carico libero era molto bassa (rapporto di massa <1:500.000). Sono previsti trial clinici globali intorno alla fine del 2025 con ulteriori filing IND nel 2026.
HUTCHMED (Nasdaq/AIM: HCM) presentó datos preclínicos para HMPL-A251 en la conferencia AACR-NCI-EORTC (del 22 al 26 de octubre de 2025). HMPL-A251 es un ATTC que combina un IgG1 anti-HER2 humanizado con un payload de inhibidor PI3K/PIKK altamente potente y selectivo mediante un linker hidrofílico cleavable. In vitro mostró una actividad amplia en 130 líneas celulares tumorales, muerte dependiente de HER2 y un efecto bystander. In vivo, una dosis única IV indujo regresión tumoral en modelos HER2-positivos y HER2-bajos, con eficacia comparable o superior a T-DXd en la mayoría de los modelos. La exposición plasmática del payload libre fue muy baja (relación masa <1:500,000). Se planifican ensayos clínicos globales alrededor de fin de 2025 con presentaciones IND adicionales en 2026.
HUTCHMED (나스닥/ AIM: HCM)은 AACR-NCI-EORTC 학회(2025년 10월 22–26일)에서 HMPL-A251의 전임상 데이터를 발표했습니다. HMPL-A251은 인간화된 항-HER2 IgG1과 강력하고 선택적인 PI3K/PIKK 억제제 페이로드를 가교하는 가변형 친수성 링커를 통해 결합된 ATTC입니다. 체외에서 130개 종양 세포주에 걸친 광범위한 활력, HER2 의존적 살상 및 바이스터 효과를 보였습니다. 체내에서 단일 정맥주사로 HER2 양성 및 HER2 저발현 모델에서 종양 억제가 유도되었고, 대다수의 모델에서 T-DXd와 비교 가능하거나 우수한 효능을 보였습니다. 자유 페이로드 혈장 노출은 매우 낮았으며 (질량비 <1:500,000)입니다. 글로벌 임상시험은 2025년 말 경으로 계획되어 있으며 추가 IND 제출은 2026년에 예정되어 있습니다.
HUTCHMED (Nasdaq/AIM: HCM) a présenté des données précliniques pour HMPL-A251 lors de la conférence AACR-NCI-EORTC (du 22 au 26 octobre 2025). HMPL-A251 est un ATTC qui combine un IgG1 anti-HER2 humanisé avec un payload d'inhibiteur PI3K/PIKK hautement puissant et sélectif via un linker hydrophile cleavable. In vitro, il a montré une activité large sur 130 lignées cellulaires tumorales, une cytotoxicité dépendante de HER2 et un effet bystander. In vivo, une dose unique IV a entraîné une régression tumorale dans des modèles HER2-positifs et HER2-faibles, avec une efficacité comparable ou supérieure à T-DXd dans la plupart des modèles. L'exposition plasmatique du payload libre était très faible (rapport masse <1:500 000). Des essais cliniques globaux sont prévus autour de fin 2025 avec des dépôts IND supplémentaires en 2026.
HUTCHMED (Nasdaq/AIM: HCM) präsentierte präklinische Daten für HMPL-A251 auf der AACR-NCI-EORTC-Konferenz (22.–26. Oktober 2025). HMPL-A251 ist ein ATTC, das einen humanisierten anti-HER2-IgG1 mit einem hochpotenten, selektiven PI3K/PIKK‑Inhibitorpayload über einen spaltbaren hydrophilen Linker verbindet. In vitro zeigte es breite Aktivität über 130 Tumorzelllinien, HER2-abhängige Tötung und einen By-stander‑Effekt. In vivo führte eine einzelne IV-Dosis zur Tumorregression in HER2-positiven und HER2-niedrig exprimierenden Modellen, mit Wirksamkeit vergleichbar oder überlegen zu T-DXd in den meisten Modellen. Die Freisetzung des Payloads im Plasma war sehr gering (Massenverhältnis <1:500.000). Globale klinische Studien sind für rund Ende 2025 geplant, mit weiteren IND-Anmeldungen im Jahr 2026.
HUTCHMED (ناسداك/ AIM: HCM) قدمت بيانات ما قبل السريرية لـ HMPL-A251 في مؤتمر AACR-NCI-EORTC (من 22 إلى 26 أكتوبر 2025). HMPL-A251 هو ATTC يجمع بين IgG1 مضاد-HER2 مُهندَس بشرياً مع حمولـة مثبِّتة لـ PI3K/PIKK عالية الفعالية وبالتحديد عبر رابط قابل للتحلل مائي. في المختبر أظهر نشاطاً واسعاً عبر 130 سلاً ورميّة، قتل يعتمد على HER2 وتأثير بايستاندر. في الجسم الحي، أدت جرعة وريدية واحدة إلى انكماش الورم في نماذج HER2‑إيجابية وHER2‑منخفضة، مع فاعلية تقارن أو تفوق T-DXd في معظم النماذج. التعرض البلازمي للحمولة الحرة كان منخفضاً جداً (نسبة الكتلة <1:500,000). تخطط التجارب السريرية العالمية نحو نهاية 2025 مع تقديمات IND إضافية في 2026.
HUTCHMED (纳斯达克/ AIM: HCM) 在 AACR-NCI-EORTC 会议（2025年10月22–26日）上公布了 HMPL-A251 的前临床数据。HMPL-A251 是一个 ATTC，将人源化的 anti-HER2 IgG1 与一个高效、选择性的 PI3K/PIKK 抑制载荷通过一个可裂解的亲水性连接子连接起来。体外在 130 种肿瘤细胞系 上显示出广谱活性、HER2 依赖性杀伤及旁观者效应。在体内，单次静脉注射在 HER2 阳性和 HER2 低表达模型中均诱导肿瘤回归，在大多数模型中的效果可与或优于 T-DXd。自由载荷的血浆暴露极低 (质量比 <1:500,000)。全球临床试验计划在 2025 年底 左右启动，2026 年还将有额外的 IND 提交。
- Broad in vitro activity across 130 tumor cell lines
- Single IV dose induced tumor regression across multiple models
- Efficacy superior or comparable to T-DXd in most tested models
- Very low free payload plasma exposure: mass ratio <1:500,000
- Company plans to start global clinical trials around end of 2025
- Preclinical only: no human safety or efficacy data yet
- Moderately reduced activity in HER2-low, PAM-altered cell lines
Insights
Preclinical HMPL-A251 shows strong HER2-targeted activity and plans for global trials around end of
HMPL-A251 pairs a humanized anti-HER2 IgG1 antibody with a selective PI3K/PIKK inhibitor payload via a cleavable, hydrophilic linker to concentrate PAM pathway inhibition in HER2-expressing tumors. Reported in vitro results show broad potency across 130 tumor lines, HER2-dependent activity, payload-driven apoptosis, and a bystander effect in co-culture. In vivo data claim tumor regression after a single IV dose in HER2-positive and HER2-low models, with efficacy correlating to tumor payload concentration and target inhibition.
The release highlights a tolerability advantage: plasma free-payload exposure was reported as much lower than for HMPL-251 (mass ratio <1:500,000), and head-to-head preclinical comparisons indicate superior or comparable efficacy versus T-DXd at equivalent doses in most models. These facts support a mechanistic rationale for improved therapeutic index, but they remain preclinical observations only.
Near-term milestones to watch are the planned initiation of global clinical trials around
— First investigational drug candidate using the HUTCHMED ATTC technology platform to create potent targeted therapy payloads while mitigating related toxicities —
— Unique, highly potent PI3K/PIKK inhibitor payload optimized to exploit antibody-conjugate advantages, with directed delivery and low plasma exposure of free payload —
— Preclinical data shows robust antitumor activity with synergistic and bystander killing effects —
HONG KONG and SHANGHAI and FLORHAM PARK, N.J., Oct. 23, 2025 (GLOBE NEWSWIRE) -- HUTCHMED (China) Limited (“HUTCHMED”) (Nasdaq/AIM:HCM; HKEX:13) today announces preclinical data for HMPL-A251 at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 22–26, 2025, in Boston, USA. HMPL-A251 is a first-in-class PI3K/AKT/mTOR (“PAM”)-HER2 Antibody-Targeted Therapy Conjugate (“ATTC”) comprising of a highly selective and potent PI3K/PIKK inhibitor payload linked to a humanized anti-HER2 IgG1 antibody, via a cleavable linker.
HER2 is a well-established therapeutic target. HER2 overexpression is found in a variety of cancer types and often associated with poor prognosis. As a key downstream signaling pathway of HER2, the PAM pathway contributes significantly to the resistance against HER2-targeting treatments when altered. HMPL-A251 is innovatively designed to leverage the synergy between HER2 targeting and PAM pathway inhibition to address limitations of traditional toxin-based antibody-drug conjugates (“ADCs”) and standalone PAM inhibitors.
In vitro, the PI3K/PIKK inhibitor payload exhibited high potency, selectivity, and broad anti-tumor activity across a panel of 130 tumor cell lines. By conjugating this potent payload with an anti-HER2 antibody via a hydrophilic linker, the ATTC compound HMPL-A251, upon binding to the HER2-positive target cells, undergoes rapid internalization, lysosomal trafficking, payload release, and inhibition of PAM and PIKK signaling, inducing tumor cell apoptosis. HMPL-A251 demonstrated HER2-dependent antitumor activity in vitro, potently inhibiting HER2-positive tumor cell growth regardless of PAM pathway alterations, with moderately reduced activity in HER2-low, PAM-altered cell lines. HMPL-A251 also demonstrated a bystander effect on HER2-null cells when co-cultured with HER2-positive cells.
Unlike toxin-based ADCs, which often face challenges with toxicity related to their cytotoxic payloads, ATTCs are designed to prioritize tumor-specific delivery of a pathway-modulating payload, enhancing safety for long-term use and enabling potential frontline combinations with chemotherapy. In vivo, HMPL-A251 demonstrated superior anti-tumor efficacy and tolerability as compared to the naked antibody and payload administered together. A single intravenous dose of HMPL-A251 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. Notably, when benchmarked against T-DXd (trastuzumab deruxtecan, a HER2-directed ADC), HMPL-A251 achieved superior or comparable efficacy at equivalent doses in most tested models. Moreover, payload-based toxicities are expected to be low, as the plasma exposure of free payload was much lower than for HMPL-251, with a mass ratio of less than 1:500,000.
“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. By combining selective PI3K/PIKK inhibition with precise HER2 targeting, HMPL-A251 achieves potent antitumor effects while maintaining a favorable safety profile,” said Dr Michael Shi, Head of R&D and Chief Medical Officer of HUTCHMED. “The compelling preclinical data presented underscore its potential to redefine treatment for a wide spectrum of cancers, and we are excited to advance HMPL-A251 as well as more ATTC drug candidates toward clinical trials.”
HUTCHMED plans to initiate global clinical trials for HMPL-A251 around the end of 2025, followed by multiple global Investigational New Drug (IND) filings for more ATTC candidates in 2026.
About the ATTC platform
HUTCHMED’s Antibody-Targeted Therapy Conjugate platform represents a next-generation approach to precision oncology, combining monoclonal antibodies with proprietary small-molecule inhibitor payloads to deliver dual mechanisms of action. Unlike traditional cytotoxin-based ADCs, ATTCs combine targeted therapies to achieve synergistic anti-tumor activity and durable responses in preclinical models, outperforming standalone antibody or small-molecule inhibitor components in efficacy and safety.
Built on over 20 years of targeted therapy expertise, the platform enables development of drug candidates for diverse cancer types. By leveraging antibody-guided delivery and tumor-specific payload release, ATTCs improve the accessibility to tumors and reduce off-tumor toxicity. This overcomes challenges of traditional small-molecule inhibitors, ensures safer long-term use, and supports combinations with chemotherapy and immunotherapy, unlocking potential for early-line treatments.
About HUTCHMED
HUTCHMED (Nasdaq/AIM:HCM; HKEX:13) is an innovative, commercial-stage, biopharmaceutical company. It is committed to the discovery and global development and commercialization of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases. Since inception it has focused on bringing drug candidates from in-house discovery to patients around the world, with its first three medicines marketed in China, the first of which is also approved around the world including in the US, Europe and Japan. For more information, please visit: www.hutch-med.com or follow us on LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the US Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect HUTCHMED’s current expectations regarding future events, including but not limited to its expectations regarding the therapeutic potential of HMPL-A251 and other drug candidates from the ATTC platform, the further clinical development for HMPL-A251 and other drug candidates from the ATTC platform, its expectations as to whether any studies on HMPL-A251 and other drug candidates from the ATTC platform would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates and the timing and availability of subjects meeting a study’s inclusion and exclusion criteria; changes to clinical protocols or regulatory requirements; unexpected adverse events or safety issues; the ability of HMPL-A251 and other drug candidates from the ATTC platform, including as combination therapies, to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions and to gain commercial acceptance after obtaining regulatory approval; the potential markets of HMPL-A251 other drug candidates from the ATTC platform for a targeted indication, and the sufficiency of funding. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see HUTCHMED’s filings with the US Securities and Exchange Commission, The Stock Exchange of Hong Kong Limited and on AIM. HUTCHMED undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.
CONTACTS
| Investor Enquiries | +852 2121 8200 / ir@hutch-med.com |
| Media Enquiries | |
| FTI Consulting – | +44 20 3727 1030 / HUTCHMED@fticonsulting.com |
| Ben Atwell / Alex Shaw | +44 7771 913 902 (Mobile) / +44 7779 545 055 (Mobile) |
| Brunswick – Zhou Yi | +852 9783 6894 (Mobile) / HUTCHMED@brunswickgroup.com |
| Panmure Liberum | Nominated Advisor and Joint Broker |
| Atholl Tweedie / Emma Earl / Rupert Dearden | +44 20 7886 2500 |
| Cavendish | Joint Broker |
| Geoff Nash / Nigel Birks | +44 20 7220 0500 |
| Deutsche Numis | Joint Broker |
| Freddie Barnfield / Jeffrey Wong / Duncan Monteith | +44 20 7260 1000 |
FAQ
What is HMPL-A251 and how does it work for investors following HCM?
When does HUTCHMED (HCM) plan to start HMPL-A251 clinical trials?
How did HMPL-A251 perform versus T-DXd in the preclinical studies presented Oct 22–26, 2025?
What safety signal did HUTCHMED report about HMPL-A251's payload exposure?
Does HMPL-A251 show activity in HER2-low or PAM-altered tumors according to HUTCHMED?
What milestones should investors watch for on HCM's HMPL-A251 program in 2026?
