BCA101 is a Tumor-Targeted Bifunctional Fusion Antibody that Simultaneously Inhibits EGFR and TGF-β Signalling to Durably Suppress Tumor Growth.

The EGFR and TGF-β signalling pathways are important mediators of tumorigenesis, and crosstalk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGF-β could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 monoclonal antibody linked to an extracellular domain of human TGF-βRII. The TGF-β "trap" fused to the light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity. Functional neutralization of TGF-β by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T and NK cell activation, while suppressing VEGF secretion. Additionally, BCA101 inhibited differentiation of naïve CD4+ T cells to inducible T-regulatory (iTreg) cells more strongly than the anti-EGFR antibody cetuximab. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGF-β "trap". TGF-β in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared to 54% in animals dosed with equimolar TGF-βRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response post dose cessation. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy.