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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 |