Reference Detail

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	10	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AMT-562		AMT 562\|AMT562	HER3 (ERBB3) Antibody 23	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
ERBB3 positive	colon cancer	sensitive	AMT-562	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AMT-562 inhibited tumor growth in a cell line xenograft model of ERBB3 (HER3)-positive colon cancer with a complete response in 4 of 5 mice and inhibited growth in patient-derived organoids in culture (PMID: 37302522).	37302522
ERBB3 positive	lung non-small cell carcinoma	sensitive	AMT-562	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AMT-562 inhibited tumor growth in a cell line xenograft model of ERBB3 (HER3)-positive non-small cell lung cancer (PMID: 37302522).	37302522
BRAF V600E ERBB3 pos	colon cancer	sensitive	AMT-562 + LY2603618	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Rabusertiv (LY2603618) and AMT-562 synergistically inhibited tumor growth in a cell line xenograft model of ERBB3 (HER3)-positive colon cancer harboring BRAF V600E (PMID: 37302522).	37302522
BRAF V487_P492delinsA ERBB3 pos	pancreatic cancer	sensitive	AMT-562	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AMT-562 inhibited growth in a cell line xenograft model of ERBB3 (HER3)-positive pancreatic cancer harboring BRAF V487_P492delinsA (PMID: 37302522).	37302522
ERBB3 positive	esophagus squamous cell carcinoma	sensitive	AMT-562	Preclinical - Pdx	Actionable	In a preclinical study, AMT-562 inhibited tumor growth in a patient-derived xenograft (PDX) model of ERBB3 (HER3)-positive esophageal squamous cell carcinoma (PMID: 37302522).	37302522
ERBB3 positive	esophagus adenocarcinoma	sensitive	AMT-562	Preclinical - Pdx	Actionable	In a preclinical study, AMT-562 inhibited tumor growth in a patient-derived xenograft (PDX) model of ERBB3 (HER3)-positive esophageal adenocarcinoma (PMID: 37302522).	37302522
ERBB3 positive	gastroesophageal junction adenocarcinoma	sensitive	AMT-562	Preclinical - Pdx	Actionable	In a preclinical study, AMT-562 inhibited tumor growth in a patient-derived xenograft (PDX) model of ERBB3 (HER3)-positive gastroesophageal junction adenocarcinoma (PMID: 37302522).	37302522
BRAF V600E ERBB3 pos	colon cancer	sensitive	AMT-562	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AMT-562 inhibited tumor growth in a cell line xenograft model of ERBB3 (HER3)-positive colon cancer harboring BRAF V600E (PMID: 37302522):	37302522
ERBB3 amp	rectum cancer	sensitive	AMT-562	Preclinical - Pdx	Actionable	In a preclinical study, AMT-562 inhibited tumor growth in a patient-derived xenograft (PDX) model of ERBB3 (HER3)-amplified rectal cancer (PMID: 37302522).	37302522
ERBB3 positive	stomach cancer	sensitive	AMT-562	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AMT-562 inhibited tumor growth in a cell line xenograft model of ERBB3 (HER3)-positive gastric cancer (PMID: 37302522).	37302522
ERBB3 positive	breast cancer	predicted - sensitive	AMT-562	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AMT-562 inhibited tumor growth in a cell line xenograft model of low ERBB3 (HER3)-expressing breast cancer (PMID: 37302522).	37302522