![]() The suboptimal clinical efficacy of cetuximab and other EGFR-targeting therapeutics was attributed to both tumor intrinsic and tumor microenvironment (TME) derived acquired (extrinsic) resistance mechanisms ( 2). For example, while Herceptin, which targets HER2-overexpressing breast cancer, has improved patient survival, anti-EGFR (which also belongs to the HER family) mAbs have had limited therapeutic benefit in the clinic ( 2). However, the therapeutic potential of mAbs remains to be fully realized. Since the 1990s, multiple therapeutic molecules involving targeted therapy have been developed and many of them were mAbs as they are naturally stable molecules, highly specific with longer half-lives ( 1). Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy. 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. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after dose cessation. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFβ “trap.” TGFβ in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFβRII-Fc. In addition, BCA101 inhibited differentiation of naïve CD4 + T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab. ![]() ![]() BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer–cell activation, while suppressing VEGF secretion. Functional neutralization of TGFβ by BCA101 was demonstrated by several in vitro assays. The TGFβ “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. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFβRII. Therapies capable of simultaneously targeting EGFR and TGFβ could help improve patient outcomes across various cancer types. The EGFR and TGFβ signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance.
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