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Ref Type Journal Article
PMID (37302522)
Authors Weng W, Meng T, Pu J, Ma L, Shen Y, Wang Z, Pan R, Wang M, Chen C, Wang L, Zhang J, Zhou B, Shao S, Qian Y, Liu SH, Hu W, Meng X
Title AMT-562, a novel HER3-targeting antibody drug conjugate, demonstrates a potential to broaden therapeutic opportunities for HER3-expressing tumors.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 2023 Jun 11 Mol Cancer Ther
URL
Abstract Text HER3 is a unique member of the epidermal growth factor receptor family of tyrosine kinases, which is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers and is often associated with poor patient outcomes and therapeutic resistance. U3-1402/Patritumab-GGFG-DXd is the first successful HER3-targeting ADC molecule with clinical efficacy in non-small cell lung cancer (NSCLC). However, over 60% of patients are non-responsive 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 Ab562 and a modified self-immolative PABC spacer (T800) to conjugate exatecan. Exatecan showed higher cytotoxic potency than its derivative DXd. Ab562 was selected due to 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 (PDX/PDO) models, including digestive system and lung tumors representing of unmet needs. Combination therapies pairing AMT-562 with therapeutic antibodies, inhibitors of CHEK1, KRAS and TKI showed higher synergistic efficacy than Patritumab-GGFG-DXd. Pharmacokinetics and safety profiles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg in cynomolgus monkeys. AMT-562 has potential to be a 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AMT-562 AMT-562 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
AMT-562 AMT 562|AMT562 HER3 (ERBB3) Antibody 28 AMT-562 is an antibody drug conjugate (ADC) comprising an ERBB3 (HER3) antibody conjugated to exatecan, which potentially inhibits tumor growth (PMID: 37302522).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References