Related Experiment Video
Updated: Oct 4, 2025
Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
Published on: April 26, 2024
Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements
Alison M Schram1,2, Igor Odintsov3,4, Madelyn Espinosa-Cotton5
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity-enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion-positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion-positive metastatic cancer were treated with Zeno. Two patients with ATP1B1-NRG1-positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74-NRG1-positive non-small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion-positive cancers.
Significance:
NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion-positive cancers and is thus an effective therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1171.
Insights
Zenocutuzumab, a novel bispecific antibody, effectively targets NRG1 fusion-positive cancers by simultaneously inhibiting HER2 and HER3. This approach shows promising durable clinical responses in patients with advanced solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- NRG1 gene rearrangements are key drivers in various solid tumors.
- NRG1 fusions activate the ERBB receptor tyrosine kinase pathway, promoting cancer growth.
- Targeting the ERBB family presents a potential therapeutic strategy for NRG1-driven cancers.
Purpose of the Study:
- To investigate the efficacy of zenocutuzumab (Zeno), an anti-HER2xHER3 bispecific antibody, in preclinical models and patients with NRG1 fusion-positive cancers.
- To evaluate Zeno's mechanism of action, including its impact on downstream signaling pathways and tumor cell apoptosis.
- To assess the clinical outcomes of patients with advanced NRG1 fusion-positive cancers treated with Zeno.
Main Methods:
- Utilized isogenic and patient-derived cell lines and xenograft models of NRG1 fusion-positive cancers.
- Administered zenocutuzumab to preclinical models and three patients with chemotherapy-resistant metastatic NRG1 fusion-positive cancers.
- Assessed HER3 and AKT phosphorylation, apoptosis markers, tumor growth inhibition, and clinical responses (symptomatic, biomarker, radiographic).
Main Results:
- Zenocutuzumab demonstrated inhibition of HER3 and AKT phosphorylation and induced apoptosis in preclinical models.
- Two patients with ATP1B1-NRG1-positive pancreatic cancer experienced rapid and durable responses, remaining on treatment for over 12 months.
- A patient with CD74-NRG1-positive non-small cell lung cancer achieved a partial response after progressing on multiple prior therapies.
Conclusions:
- Simultaneous targeting of HER2 and HER3 with zenocutuzumab is a novel and effective therapeutic strategy for NRG1 fusion-positive cancers.
- Zenocutuzumab shows significant potential for treating patients with advanced, treatment-resistant solid tumors driven by NRG1 fusions.
- The findings support zenocutuzumab as a promising therapeutic paradigm in oncology.
More Related Videos
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:27Tumor Immunotherapy
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
02:56Treatment Resistant Cancers
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...