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Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to
Srinivas Reddy Boreddy1, Reshmi Nair1, Prashant Kumar Pandey1
1Biofusion Therapeutics, Bengaluru, India.
Abstract:
The EGFR and TGFβ 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 TGFβ 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 TGFβRII. 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. Functional neutralization of TGFβ 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 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 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 TGFβ to induce immune activation and to suppress tumor growth.
Insights
A novel bifunctional antibody, BCA101, simultaneously targets Epidermal Growth Factor Receptor (EGFR) and Transforming Growth Factor beta (TGFβ). This dual-action therapy shows promise in activating anti-tumor immunity and improving cancer treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Epidermal Growth Factor Receptor (EGFR) and Transforming Growth Factor beta (TGFβ) signaling pathways are crucial in cancer progression and drug resistance.
- Cross-talk between EGFR and TGFβ pathways exacerbates tumor growth and treatment failure.
Purpose of the Study:
- To develop and evaluate BCA101, a novel bifunctional antibody targeting both EGFR and TGFβ.
- To assess BCA101's efficacy in preclinical cancer models, including its impact on tumor microenvironment and immune activation.
Main Methods:
- Development of BCA101, an anti-EGFR IgG1 mAb fused with a TGFβ receptor II (TGFβRII) extracellular domain.
- In vitro assays to confirm TGFβ neutralization and assess effects on immune cell activation markers.
- In vivo studies using xenograft and syngeneic mouse models to evaluate tumor localization, TGFβ neutralization, and therapeutic efficacy, including combination with anti-PD1 therapy.
Main Results:
- BCA101 effectively binds EGFR and neutralizes TGFβ without steric hindrance.
- BCA101 demonstrated potent in vitro inhibition of cancer cell proliferation and induction of immune cell activation.
- In vivo studies showed BCA101's tumor localization, significant TGFβ neutralization in tumors, and durable responses in head and neck squamous cell carcinoma models.
- Combination therapy with anti-PD1 enhanced tumor inhibition in preclinical models.
Conclusions:
- BCA101 is a promising bifunctional antibody with the potential to overcome resistance mechanisms mediated by EGFR and TGFβ signaling.
- BCA101 demonstrates immunomodulatory effects, enhancing anti-tumor immunity.
- Clinical development of BCA101 as a monotherapy or in combination with immune checkpoint inhibitors is warranted.
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