Sustained Tumor Regression With Zenocutuzumab, a Bispecific Antibody Targeting Human Epidermal Growth Factor Receptor 2/Human Epidermal Growth Factor Receptor 3 Signaling, in NRG1 Fusion–Positive, Estrogen Receptor–Positive Breast Cancer After Progression on a Cyclin-Dependent Kinase 4/6 Inhibitor

Fontana, Elisa; Torga, Gonzalo; Fostea, Raluca Maria; Cleator, Susan; Wasserman, Ernesto; Murat, Anastasia; Arkenau, Hendrik‐Tobias

doi:10.1200/po.21.00446

Cited by 4 publications

(6 citation statements)

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“…72 The modified Bispecific antibodies targeting HER2 × CD3 (ertumaxomab), HER2 × CD16, and HER2 × HER3 (zenocutuzumab: MCLA-128 and MM-111) are being developed in addition to naive antibodies. [73][74][75][76][77][78] Recently, progress has been made in the creation of bispecific antibodies that target both the immune checkpoint molecules PD-1/ PD-L1 and HER2, with antitumor effects proven in preclinical animals. 79,80 In trastuzumab-resistant cancer models, bispecific antibodies targeting immune checkpoint molecules and HER2 may be more successful than individual mAb treatments.…”

Section: Discussionmentioning

confidence: 99%

“…Bispecific antibodies targeting HER2 × CD3 (ertumaxomab), HER2 × CD16, and HER2 × HER3 (zenocutuzumab: MCLA‐128 and MM‐111) are being developed in addition to naive antibodies 73–78 . Recently, progress has been made in the creation of bispecific antibodies that target both the immune checkpoint molecules PD‐1/PD‐L1 and HER2, with antitumor effects proven in preclinical animals 79,80 .…”

Section: Discussionmentioning

confidence: 99%

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Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H₂Mab‐77‐mG_2a‐f

Tanaka,

Suzuki,

Ohishi

et al. 2023

Cancer Science

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Breast cancer patients with high levels of human epidermal growth factor receptor 2 (HER2) expression have worse clinical outcomes. Anti‐HER2 monoclonal antibody (mAb) is the most important therapeutic modality for HER2‐positive breast cancer. We previously immunized mice with the ectodomain of HER2 to create the anti‐HER2 mAb, H2Mab‐77 (mouse IgG1, kappa). This was then altered to produce H2Mab‐77‐mG2a‐f, an afucosylated mouse IgG2a. In the present work, we examined the reactivity of H2Mab‐77‐mG2a‐f and antitumor effects against breast cancers in vitro and in vivo. BT‐474, an endogenously HER2‐expressing breast cancer cell line, was identified by H2Mab‐77‐mG2a‐f with a strong binding affinity (a dissociation constant [KD]: 5.0 × 10−9 M). H2Mab‐77‐mG2a‐f could stain HER2 of breast cancer tissues in immunohistochemistry and detect HER2 protein in Western blot analysis. Furthermore, H2Mab‐77‐mG2a‐f demonstrated strong antibody‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity (CDC) for BT‐474 cells. MDA‐MB‐468, a HER2‐negative breast cancer cell line, was unaffected by H2Mab‐77‐mG2a‐f. Additionally, in the BT‐474‐bearing tumor xenograft model, H2Mab‐77‐mG2a‐f substantially suppressed tumor development when compared with the control mouse IgG2a mAb. In contrast, the HER2‐negative MDA‐MB‐468‐bearing tumor xenograft model showed no response to H2Mab‐77‐mG2a‐f. These findings point to the possibility of H2Mab‐77‐mG2a‐f as a treatment regimen by showing that it has antitumor effects on HER2‐positive breast tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H₂Mab‐77‐mG_2a‐f

Tanaka,

Suzuki,

Ohishi

et al. 2023

Cancer Science

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“…Bispecific antibodies targeting HER2×CD3 (ertumaxomab), HER2×CD16, and HER2×HER3 (zenocutuzumab: MCLA-128 and MM-111) are being developed in addition to naive antibodies [69][70][71][72][73][74]. Recently, progress has been made in the creation of bispecific antibodies that target both the immune checkpoint molecules PD-1/PD-L1 and HER2, with antitumor effects proven in preclinical animals [75,76].…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activities against Breast Cancers by an Afucosylated Anti-HER2 Monoclonal Antibody H2Mab-77-mG2a-f

Tanaka¹,

Suzuki²,

Ohishi³

et al. 2023

Preprint

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Breast cancer patients with high levels of HER2 (human epidermal growth factor receptor 2) expression had worse clinical outcomes. Anti-HER2 monoclonal antibody (mAb) is the most important therapeutic modality for HER2-positive breast cancer. We previously immunized mice with the ectodomain of HER2 to create the anti-HER2 mAb, H2Mab-77 (mouse IgG1, kappa). This was then altered to produce H2Mab-77-mG2a-f, an afucosylated mouse IgG2a. In the present work, we examined the reactivity of H2Mab-77-mG2a-f and antitumor effects against breast cancers in vitro and in vivo. BT-474, an endogenously HER2-expressed breast cancer cell line, was identified by H2Mab-77-mG2a-f with a strong binding affinity [a dissociation constant (KD): 5.0 × 10-9 M]. H2Mab-77-mG2a-f could stain HER2 of breast cancer tissues in immunohistochemistry and detect HER2 protein in western blot analysis. Furthermore, H2Mab-77-mG2a-f demonstrated strong antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) for BT-474 cells. MDA-MB-468, a HER2-negative breast cancer cell line, was unaffected by H2Mab-77-mG2a-f. Additionally, in the BT-474-bearing tumor xenograft model, H2Mab-77-mG2a-f substantially suppressed tumor development when compared to the control mouse IgG2a mAb. In contrast, the HER2-negative MDA-MB-468-bearing tumor xenograft model showed no response to H2Mab-77-mG2a-f. These findings point to the possibility of H2Mab-77-mG2a-f as a treatment regimen by showing that it has antitumor effects on HER2-positive breast tumors.

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“… 53 In a clinical trial involving NRG1 fusion-positive/estrogen receptor-positive breast cancer patients who had experienced disease progression after treatment with cyclin-dependent kinase 4/6 inhibitors, zenocutuzumab demonstrated sustained tumor regression. 54 The I/II phase eNRGy clinical trial (NCT02912949) included patients with NRG1 fusions in three cohorts: NSCLC (25 cases), pancreatic cancer (13 cases), and other solid tumors (13 cases). The results of the study showed excellent efficacy of zenocutuzumab in pancreatic cancer patients, with a partial response observed in 42% (5/12) of patients, stable disease in 6 cases, and disease progression in only 1 case.…”

Section: Treatment Strategies For Nrg1/nrg2 Fusionmentioning

confidence: 99%

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors

Xu,

Wang,

Wang

et al. 2024

Glob Med Genet

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The fusion genes NRG1 and NRG2, members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1-positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2. Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

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Abstract: Creative Commons Attribution Non-Commercial No Derivatives 4.0 License Author affiliations and support information (if applicable) appear at the end of this article.

Cited by 4 publications

References 25 publications

Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H₂Mab‐77‐mG_2a‐f

Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H₂Mab‐77‐mG_2a‐f

Antitumor Activities against Breast Cancers by an Afucosylated Anti-HER2 Monoclonal Antibody H<sub>2</sub>Mab-77-mG<sub>2a</sub>-f

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors

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Abstract: Creative Commons Attribution Non-Commercial No Derivatives 4.0 License Author affiliations and support information (if applicable) appear at the end of this article.

Cited by 4 publications

References 25 publications

Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H2Mab‐77‐mG2a‐f

Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H2Mab‐77‐mG2a‐f

Antitumor Activities against Breast Cancers by an Afucosylated Anti-HER2 Monoclonal Antibody H<sub>2</sub>Mab-77-mG<sub>2a</sub>-f

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors

Contact Info

Product

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Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H₂Mab‐77‐mG_2a‐f

Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H₂Mab‐77‐mG_2a‐f