Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements

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 ADCC-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 chemotherapy-resistant NRG1 fusion-positive metastatic cancer patients 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 CD74-NRG1-positive NSCLC patient 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. Statement of significanceNRG1 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.Research.

An Anti-EpCAM Monoclonal Antibody (EpMab-37-mG2a-f) Exerts Antitumor Activity against Breast Cancer in Mouse Xenograft Model

“…MCLA-128 can inhibit heregulin (a HER3 ligand)-mediated signaling of HER2/HER3 heterodimer, and suppress tumor cell growth via the suppression of PI3K/Akt signaling [51]. Clinical studies on MCLA-128 are ongoing in patients with breast cancer, pancreatic cancer, and non-small cell lung cancers [52]. In the future study, we would like to apply EpMab-37 for the combination therapy with anti-HER2 mAbs or develop a bispecific mAb targeting EpCAM and HER2.…”

Therapeutic Landscape of Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

“…MCLA-128 is a humanized bispecific antibody that contains two arms (“dock” HER2 arm and “block” HER3 arm) and targets extracellular domains, which prevents the phosphorylation of HER3 and downstream oncogenic signaling. 32 In a phase I trial, large doses of MCLA-128 were administered to ten patients with breast cancer, and the results revealed a considerable clinical benefit rate of 70%. Another phase II trial (NCT03321981) is proceeding.…”

Regulation of Signaling from the Epidermal Growth Factor Family

“…A recent report indicates that patients with metastatic breast cancer, even those with low levels of HER2, had improved survival rates , when treated with trastuzumab conjugated to the toxin deruxtecan . Bispecific antibodies against EGFR:HER2 or HER2:HER3 also have the potential to improve cancer therapy; however, it is clear that much more information on the signaling systems driving individual cancers is required for targeted therapies to become more effective. The development of techniques to grow and interrogate each patient’s tumor , is likely to empower both the generation of new targeting agents and the selection of the most appropriate drug combinations for each patient …”