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

Weng, Weining; Meng, Tao; Pu, Junyi; Ma, Linjie; Shen, Yi; Wang, Zhaohui; Pan, Rong; Wang, Mingqiao; Chen, Caiwei; Wang, Lijun; Zhang, Jianjian; Zhou, Biao; Shao, Siyuan; Qian, Yu; Liu, Shu-Hui; Hu, Wenhao; Meng, Xun

doi:10.1158/1535-7163.mct-23-0198

Cited by 9 publications

(6 citation statements)

References 49 publications

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“…An anti-HER3 mAb, Ab562, possesses ≈10-fold lower affinity (K D : 2~3 × 10 −8 M) than patritumab. The ADC AMT-562 exhibited sufficient antitumor effects with minimizing potential toxicity [34]. Since H 2 Mab-250 exhibited no reactivity to normal epithelial cells in flow cytometry (Figure 1) and IHC [22], H 2 Mab-250 or H 2 Mab-250-ADC could exhibit antitumor efficacy with lower side effects.…”

Section: Discussionmentioning

confidence: 99%

A Cancer-Specific Monoclonal Antibody against HER2 Exerts Antitumor Activities in Human Breast Cancer Xenograft Models

Kaneko,

Suzuki,

Ohishi

et al. 2024

IJMS

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Monoclonal antibody (mAb)-based and/or cell-based immunotherapies provide innovative approaches to cancer treatments. However, safety concerns over targeting normal cells expressing reactive antigens still exist. Therefore, the development of cancer-specific mAbs (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy is required to minimize the adverse effects. We previously screened anti-human epidermal growth factor receptor 2 (HER2) mAbs and successfully established a cancer-specific anti-HER2 mAb, H2Mab-250/H2CasMab-2 (IgG1, kappa). In this study, we showed that H2Mab-250 reacted with HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells in flow cytometry. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, recognized both breast cancer and normal epithelial cells. We further compared the affinity, effector activation, and antitumor effect of H2Mab-250 with trastuzumab. The results showed that H2Mab-250 exerted a comparable antitumor effect with trastuzumab in the mouse xenograft models of BT-474 and SK-BR-3, although H2Mab-250 possessed a lower affinity and effector activation than trastuzumab in vitro. H2Mab-250 could contribute to the development of chimeric antigen receptor-T or antibody–drug conjugates without adverse effects for breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

A Cancer-Specific Monoclonal Antibody against HER2 Exerts Antitumor Activities in Human Breast Cancer Xenograft Models

Kaneko,

Suzuki,

Ohishi

et al. 2024

IJMS

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“…AMT-562 has more profound and long-lasting anticancer responses in low HER3 expression cell lines and pancreatic, esophagus, colon, and gastric cancer models. AMT-562 has great pharmacokinetic and safety profiles, and its wider therapeutic window allows it to conquer resistance to elicit higher percentages and longer-lasting responses in malignancies resistant to U3-1402 [ 120 ] . Based on the superiority of AMT-562 in cancer treatment, it is starting to be studied in clinical malignancies.…”

Section: The Development Of Her3 Targeting Cancer Therapymentioning

confidence: 99%

HER3-targeted therapy: the mechanism of drug resistance and the development of anticancer drugs

Zeng,

Wang,

Zhang

et al. 2024

Cancer Drug Resist

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Human epidermal growth factor receptor 3 (HER3), which is part of the HER family, is aberrantly expressed in various human cancers. Since HER3 only has weak tyrosine kinase activity, when HER3 ligand neuregulin 1 (NRG1) or neuregulin 2 (NRG2) appears, activated HER3 contributes to cancer development and drug resistance by forming heterodimers with other receptors, mainly including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Inhibition of HER3 and its downstream signaling, including PI3K/AKT, MEK/MAPK, JAK/STAT, and Src kinase, is believed to be necessary to conquer drug resistance and improve treatment efficiency. Until now, despite multiple anti-HER3 antibodies undergoing preclinical and clinical studies, none of the HER3-targeted therapies are licensed for utilization in clinical cancer treatment because of their safety and efficacy. Therefore, the development of HER3-targeted drugs possessing safety, tolerability, and sensitivity is crucial for clinical cancer treatment. This review summarizes the progress of the mechanism of HER3 in drug resistance, the HER3-targeted therapies that are conducted in preclinical and clinical trials, and some emerging molecules that could be used as future designed drugs for HER3, aiming to provide insights for future research and development of anticancer drugs targeting HER3.

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“…The HER3/HER2 and HER3/EGFR axes can be triggered in TNBC by different factors, such as upregulation of neuregulin or EGFR (21,22,86). It is associated with a poor prognosis and therapeutic resistance (21,87,88). However, the blockage of HER3 did not show any clinical benefit.…”

Section: Other Adcs Under Investigationmentioning

confidence: 99%

“…However, the blockage of HER3 did not show any clinical benefit. In this scenario, ongoing trials investigate a promising strategy using the ADC patritumab deruxtecan (87,88) The folate receptor alpha (FRa) protein is a member of the FR family, and it is located on cell membranes. FRa binds to folic acid and its derivatives, which becomes crucial during fetal development.…”

Section: Other Adcs Under Investigationmentioning

confidence: 99%

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Triple-negative breast cancer: from none to multiple therapeutic targets in two decades

Carvalho

2023

Front. Oncol.

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Triple-negative breast cancers (TNBCs) are more likely to occur in younger patients and have a poor prognosis. They are highly heterogeneous tumors consisting of different molecular subtypes. The only common characteristic among them is the absence of targets for endocrine therapy and human epidermal growth factor receptor 2 (HER2) blockade. In the past two decades, there has been an increased understanding of these tumors from a molecular perspective, leading to their stratification according to new therapeutic strategies. TNBC has ushered breast carcinomas into the era of immunotherapy. The higher frequency of germline BRCA mutations in these tumors enables targeting this repair defect by drugs like PARP inhibitors, resulting in synthetic lethality in neoplastic cells. Additionally, we have the identification of new molecules to which this generation of smart drugs, such as antibody-drug conjugates (ADCs), are directed. In this review, we will discuss the trajectory of this knowledge in a systematic manner, presenting the molecular bases, therapeutic possibilities, and biomarkers.

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

Cited by 9 publications

References 49 publications

A Cancer-Specific Monoclonal Antibody against HER2 Exerts Antitumor Activities in Human Breast Cancer Xenograft Models

A Cancer-Specific Monoclonal Antibody against HER2 Exerts Antitumor Activities in Human Breast Cancer Xenograft Models

HER3-targeted therapy: the mechanism of drug resistance and the development of anticancer drugs

Triple-negative breast cancer: from none to multiple therapeutic targets in two decades

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