AMT-562, a Novel HER3-targeting Antibody–Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors

Q: Why is HER3 a challenging therapeutic target?

HER3 is broadly expressed and linked to poor outcomes and resistance, but it cannot be inhibited effectively by classical ATP-analog kinase inhibitors. Blocking generally requires targeting its extracellular domain with antibodies or antibody-based therapeutics.

Q: How is AMT-562 constructed and what drug does it deliver?

AMT-562 combines a novel anti-HER3 antibody (Ab562) with a modified self-immolative PABC spacer (T800) conjugated to exatecan. The design uses exatecan to achieve higher cytotoxic potency than a related derivative.

Q: What evidence supports AMT-562’s potential to improve outcomes versus U3-1402?

AMT-562 shows potent and durable antitumor responses in low-HER3 expression xenografts and heterogeneous patient-derived models, including digestive system and lung tumors. It also demonstrates stronger or synergistic effects in combination settings and has favorable pharmacokinetic and safety profiles, suggesting an improved therapeutic window.

Sep 24, 2026

Uploaded by Bintang

HER3 is a widely expressed EGFR-family pseudokinase linked to poor outcomes and therapeutic resistance across multiple cancers, yet the first successful HER3-targeting ADC, U3-1402/Patritumab-GGFG-DXd, shows limited responsiveness. AMT-562 was engineered from a novel anti-HER3 antibody (Ab562) and a modified self-immolative PABC spacer (T800) conjugated to exatecan. In low-HER3 and heterogeneous xenograft/PDX/organoid models, AMT-562 produced potent, durable antitumor effects, with favorable pharmacokinetic and safety profiles, including the highest tested tolerated dose. Combination regimens exhibited stronger synergy than Patritumab-GGFG-DXd, supporting AMT-562’s potential to overcome resistance.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

HER3 and therapeutic challenges

AMT-562 design and mechanism

Preclinical efficacy and model types

Combination strategies and results

Pharmacokinetics and safety

FIRST DISCLOSURE AMT-562, a Novel HER3-targeting Antibody–Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors Weining Weng1,2, Tao Meng3,4, Junyi Pu5, Linjie Ma2, Yi Shen2, Zhaohui Wang6, Rong Pan6, Mingqiao Wang6, Caiwei Chen2, Lijun Wang2, Jianjian Zhang2, Biao Zhou2, Siyuan Shao7, Yu Qian1, Shuhui Liu2, Wenhao Hu1, and Xun Meng2,6 ABSTRACT | ◥ | HER3 is a unique member of the EGFR family of tyrosine kinases, which is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancersand is often associated with poor patient outcomes and therapeutic resistance. U3-1402/Patritumab-GGFG-DXd is the ﬁrst successful HER3-targeting antibody–drug conjugate (ADC) with clinical efﬁcacyin non–small cell lung cancer. However, over60% ofpatients are nonresponsive to U3-1402 due to low target expression levels and responses tend to be in patients with higher target expression levels. U3-1402 is also ineffective in more challenging tumor types such as colorectal cancer. AMT-562 was generated by a novel anti-HER3 antibody Ab562and a modiﬁed self-immolative PABC spacer(T800) to conjugate exatecan. Exatecan showed higher cytotoxic potency than its derivative DXd. Ab562 was selected because of its moderate afﬁnity for minimizing potential toxicity and improving tumor penetration purposes. Both alone or in combination therapies, AMT-562 showed potent and durable antitumor response in low HER3 expression xenograft and heterogeneous patient-derived xenograft/ organoid models, including digestive system and lung tumors representing of unmet needs. Combination therapies pairing AMT-562 | with therapeutic antibodies, inhibitors of CHEK1, KRAS, and tyrosine kinase inhibitor showed higher synergistic efﬁcacy than Patritumab-GGFG-DXd. Pharmacokinetic and safety proﬁles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg incynomolgus monkeys. AMT-562 has potential tobea superior HER3-targeting ADC with a higher therapeutic window that can overcome resistance to generate higher percentage and more durable responses in U3-1402–insensitive tumors. | | | | | | --- | --- | --- | --- | --- | --- | --- | | | | MC VA T moiety Exatecan Exatecan | | | 1500
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00-20-40 -60 -80 -100 | | | | | | | | | | | | | AMT-562: a HER3-targeting ADC using TOP I inhibitor exatecan | | | | | | | | | | | A549 PC9 H1975 H2170 361019 390629 200730 361646 200717 200662
AMT-562 shows superior efficacy to P-GGFG-DXd in NSCLC | | | | | 800
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| | | | | | | | AMT-562 is more effective in CRC | AMT-562 demonstrates stronger synergy in CRC | | | | T800： X=CH2-NH-CH3 Tumor volume change from baseline (%) Tumor volume (mm3) (mean±SEM) Tumor volume change from baseline (%) KRAS G12C BRA F V600E CD74-ROS1 fusion ROS1 G2032R TP53 R158G TP53 R273H PI K3CA G118D KRAS G12S ****p<0. 0001 **p 0.0028 Introduction HER3 is a unique member of the EGFR family of tyrosine kinases (ErbB; refs. 1, 2). It is a pseudokinase lacking signiﬁcant kinase activity and requires heterodimerization with other members of ErbB family to activate downstream signaling pathways (1, 3, 4). HER3 is broadly expressed in solid tumors such as breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers and is often associated with 1Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, P. R. China. 2Multitude Therapeutics, Shanghai, P. R. China. 3MabCare Therapeutics, Shanghai, P. R. China. 4HySlink Therapeutics, Shanghai, P. R. China. 5School of Life Sciences, Northwest University, Xi’an, Shaanxi, P. R. China. 6Abmart Inc, Shanghai, P. R. China. 7Shanghai OneTar Biomedicine, Shanghai, P. R. China. Corresponding Authors: Xun Meng, Multitude Therapeutics, 3rd ﬂoor Bui

FAQs

Why is HER3 a challenging therapeutic target?

HER3 is broadly expressed and linked to poor outcomes and resistance, but it cannot be inhibited effectively by classical ATP-analog kinase inhibitors. Blocking generally requires targeting its extracellular domain with antibodies or antibody-based therapeutics.

How is AMT-562 constructed and what drug does it deliver?

AMT-562 combines a novel anti-HER3 antibody (Ab562) with a modified self-immolative PABC spacer (T800) conjugated to exatecan. The design uses exatecan to achieve higher cytotoxic potency than a related derivative.

What evidence supports AMT-562’s potential to improve outcomes versus U3-1402?

AMT-562 shows potent and durable antitumor responses in low-HER3 expression xenografts and heterogeneous patient-derived models, including digestive system and lung tumors. It also demonstrates stronger or synergistic effects in combination settings and has favorable pharmacokinetic and safety profiles, suggesting an improved therapeutic window.

Sep 24, 2026

Uploaded by Bintang