On December 4, 2024, Merus announced FDA accelerated approval for its HER2/HER3 bispecific antibody Zenocutuzumab (brand name Bizengri) for treating advanced pancreatic cancer and non-small cell lung cancer (NSCLC) with NRG1 gene fusions. This milestone not only ended the 30-year void in HER3-targeted therapies but also pioneered the use of bispecific antibodies in regulating dynamic signaling networks. The success of Zenocutuzumab provides multifaceted scientific insights for the biomedical field, from clinical data to molecular mechanisms, and from technology platforms to industry impact.

Clinical Data Overview: Dual Breakthrough in Efficacy and Safety

The approval of Zenocutuzumab was based on the pivotal eNRGy trial (NCT02912949), which enrolled patients with advanced NRG1 fusion-positive solid tumors who had failed previous treatments. The treatment regimen was 750mg intravenous injection every two weeks. Among 79 NSCLC patients, 72% had received chemotherapy, and 11% had used afatinib. The main fusion partners were CD74 (34%) and SLC3A2 (28%). The treatment achieved an objective response rate (ORR) of 37.2% with a median duration of response (DOR) of 14.9 months. Tumor burden significantly decreased in 82% of patients, and 78% of pancreatic cancer patients showed over 50% reduction in CA19-9 levels. Among 33 pancreatic cancer patients, 42.4% achieved an objective response (including one complete response), with a median DOR of 9.1 months, and 72.7% achieved clinical benefit. Regarding safety, grade 3 or higher adverse events occurred in only 6% of patients, with no treatment-related discontinuations. The main adverse reactions were diarrhea (21%) and injection reactions (18%). These data demonstrate that Zenocutuzumab significantly extends response duration while breaking away from traditional targeted therapy's dependence on biomarkers, with its efficacy stemming from precise blockade of the HER2/HER3 signaling pathway.

Fig 1. Zenocutuzumab clinical information

Molecular Design Logic: From Dynamic Inhibition to Structural Innovation

Within the HER family, HER3 was long considered a marginal player. Unlike HER2, which revolutionized breast cancer treatment, HER3 remained undruggable for 30 years due to its lack of intrinsic kinase activity, strong ligand dependence, and absence of clear biomarkers. The core challenge lay in the fact that after ligand NRG1 binds to HER3, it must form heterodimers with HER2 to activate downstream signaling - a dynamic interaction difficult to block with traditional monoclonal antibodies. The turning point came with understanding the mechanism of NRG1 gene fusion. Research revealed that NRG1 fusion proteins act as "super ligands," bypassing normal regulation to activate HER3 continuously, driving the progression of solid tumors like pancreatic and lung cancer.

Fig 2. Diagram of HER2-HER3 heterodimerization and downstream signaling activation regulating cell proliferation, survival, apoptosis, tumor growth, and metastasis.

Zenocutuzumab's design directly addresses HER3's challenges by blocking both NRG1-HER3 binding and HER2/HER3 dimerization. The Merus team employed a "Dock & Block" strategy: using IgG domains to anchor to HER2's extracellular domain IV while utilizing scFv fragments to block HER3's ligand binding site, creating a three-dimensional blockade. This design enables the drug to inhibit NRG1-induced signaling at nanomolar concentrations, showing a hundred-fold improved potency over traditional antibodies.

Fig 3. The systematic development of Zenocutuzumab.

The research team built antibody libraries through multi-modal immunization of C57/BL6 mice (cells, proteins, DNA), selecting 63 HER2-binding and 117 HER3-binding clones. Using Merus's proprietary Biclonics^® platform, they assembled bispecific antibodies. The platform resolves chain mispairing through DEKK mutations (D351/E368 and K351/K366 in the CH3 heavy chain region) combined with common light chain technology to ensure product uniformity. Among 545 candidate bispecific antibodies, PB3566 stood out.

Fig 4. Design HER2xHER3 bispecific IgG with CH3 "DEKK," assess growth inhibition in BxPC-3 cells, and analyze proliferation changes with/without HRG.

PB3566 (later optimized to MCLA-128) binds to the C-terminal of HER2 extracellular domain I (residues 143-181) and HER3 domain III's Y424-N425-R426 loop structure, forming a 140Å spatial blockade that directly competitively inhibits NRG1 ligand binding. Structural biology shows that HER2 binding relies mainly on heavy chain CDRs, while HER3 blockade is achieved through light and heavy chain cooperation.

Fig 5. Structural investigation of model of binding.

In functional validation, Zenocutuzumab completely inhibited HER3 phosphorylation even in high 10nM HRG conditions, while avoiding the cardiac toxicity risk associated with combining trastuzumab with anthracyclines. The low fucose version (PB4188 LF) showed significantly improved tumor inhibition compared to T-DM1 (p<0.001) in resistant models, confirming the therapeutic potential of ADCC optimization.

Fig 6. Superior anti-tumor effects of PB4188LF.

Platform Technology and Industry Impact: The Comeback Path for Long-Tail Targets

This technical breakthrough provides a new paradigm for bispecific antibody development. Common light chain and DEKK mutations control mispairing rates below 5%, while epitope-guided screening strategies (focusing on HER2 domain I and HER3 domain III) achieve optimal regulation of dynamic signaling networks. The platform has spawned other candidate drugs like the EGFR/c-MET bispecific antibody MCLA-129, which has shown a preliminary 41% ORR in MET-amplified NSCLC. Zenocutuzumab's success has driven industry chain upgrades: RNA-based NGS detection sensitivity must reach below 0.1%, pushing molecular diagnostics into an "ultra-trace era." Preclinical studies suggest its combination with HER2 CAR-T can increase tumor microenvironment penetration by 60%, opening new directions for cell therapy combinations. However, challenges remain - single-cell sequencing revealed MET amplification resistance mechanisms require developing next-generation HER3/MET bispecific antibodies while improving toxin delivery efficiency in bispecific ADCs still faces key technical bottlenecks like optimizing endocytosis pathways.

Future Outlook: From Scientific Breakthrough to Clinical Ecosystem Reconstruction

Zenocutuzumab's approval is just the beginning of HER3-targeted therapy. Expansion to breast cancer, colorectal cancer, and other NRG1 fusion tumor types is being explored. In manufacturing, controlling batch-to-batch consistency of bispecific antibodies (especially maintaining aggregate content<0.5%) still needs a breakthrough. For combination treatment strategies, trials with HER2 ADC or MEK inhibitors are being planned to overcome existing resistance mechanisms. Notably, Merus is advancing bispecific ADC development, leveraging bispecific antibodies' high selectivity to improve toxin targeting, with preliminary data showing superior in vitro efficacy compared to traditional ADCs.

The emergence of Zenocutuzumab marks a new era in cancer treatment, shifting from "static target blockade" to "dynamic signaling network regulation." It represents not only the scientific community's victory in understanding HER family signaling complexity but also reflects the co-evolution of engineering technology, clinical development, and industrial ecology. As gene detection technology becomes more widespread and bispecific platforms iterate, more "undruggable" targets may see breakthroughs. At the core of this revolution remains the deepest understanding of disease mechanisms and the most precise response to patient needs.

Related Services at Creative Biogene

Creative Biogene provides bispecific antibody development services to design precise and high-affinity dual-target therapeutics. At the forefront of biotechnology, successful complex antibody screening relies on high-throughput antibody library construction technology. By integrating phage display and single B cell sequencing, Creative Biogene's team rapidly identifies high-affinity and highly specific candidate molecules. Working with fully human antibody platforms, we reduce antibody development cycles by 40% through AI pre-screening and wet lab experiments.

Furthermore, high-precision gene editing tools have become increasingly crucial. Using novel lentiviral vectors, Creative Biogene's Gene-Editing Platform achieves gene knock-in efficiency exceeding 90% and an editing success rate above 95%, ensuring reliable target mechanism research. In the CMC phase, our serum-free suspension culture technology employs metabolic regulation to achieve CHO cell densities of 1.5×10⁷ cells/mL while maintaining antibody aggregate content below 0.3%.