BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFß Signaling to Durably Suppress Tumor Growth.

The EGFR and TGFß signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFß could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFßRII. The TGFß "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 TGFß by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer-cell activation, while suppressing VEGF secretion. 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 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFß "trap." TGFß in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFßRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after 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. SIGNIFICANCE: The bifunctional mAb fusion design of BCA101 targets it to the tumor microenvironment where it inhibits EGFR and neutralizes TGFß to induce immune activation and to suppress tumor growth.

Design of Enzyme Loaded W/O Emulsions by Direct Membrane Emulsification for CO2 Capture.

Membrane-based gas separation is a promising unit operation in a low-carbon economy due to its simplicity, ease of operation, reduced energy consumption and portability. A methodology is proposed to immobilise enzymes in stable water-in-oil (W/O) emulsions produced by direct membrane emulsification systems and thereafter impregnated them in the pores of a membrane producing emulsion-based supported liquid membranes. The selected case-study was for biogas (CO2 and CH4) purification. Upon initial CO2 sorption studies, corn oil was chosen as a low-cost and non-toxic bulk phase (oil phase). The emulsions were prepared with Nadir® UP150 P flat-sheet polymeric membranes. The optimised emulsions consisted of 2% Tween 80 (w/w) in corn oil as the continuous phase and 0.5 g.L-1 carbonic anhydrase enzyme with 5% PEG 300 (w/w) in aqueous solution as the dispersed phase. These emulsions were impregnated onto a porous hydrophobic PVDF membrane to prepare a supported liquid membrane for gas separation. Lastly, gas permeability studies indicated that the permeability of CO2 increased by ~15% and that of CH4 decreased by ~60% when compared to the membrane without carbonic anhydrase. Thus, a proof-of-concept for enhancement of CO2 capture using emulsion-based supported liquid membrane was established.