肿瘤细胞治疗研究
英文原题：BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth.
这些结果支持BCA101作为单一疗法以及与免疫检查点疗法联合使用的临床开发。
EGFR 和 TGFβ 信号通路是肿瘤发生的重要介质，二者之间的交互作用促进癌症进展和耐药。能够同时靶向 EGFR 和 TGFβ 的治疗方法可能有助于改善多种癌症类型的患者预后。在此，我们开发了 BCA101，一种抗 EGFR IgG1 mAb，与人 TGFβRII 的胞外域连接。BCA101 中融合到轻链上的 TGFβ“陷阱”在空间上不干扰其结合 EGFR、抑制细胞增殖或介导抗体依赖性细胞毒性的能力。BCA101 对 TGFβ 的功能性中和已通过多项体外试验证实。BCA101 增加了促炎细胞因子以及与 T 细胞和NK 细胞活化相关的关键标志物的产生，同时抑制 VEGF 分泌。此外，BCA101 比抗 EGFR 抗体 cetuximab 更强地抑制 naïve CD4+ T 细胞向诱导性调节性 T 细胞（iTreg）分化。在异种移植小鼠模型中，BCA101 定位于肿瘤组织，其动力学与 cetuximab 相当，二者均比 TGFβ“陷阱”具有更好的肿瘤组织滞留。在给予 10 mg/kg BCA101 的动物中，肿瘤中的 TGFβ 被中和约 90%，而在给予等摩尔 TGFβRII-Fc 的动物中为 54%。在头颈部鳞状细胞癌患者来源异种移植小鼠模型中，BCA101 在停止给药后显示出持久缓解。BCA101 与抗 PD1 抗体的联合在表达 B16-hEGFR 的同系小鼠模型以及携带人 PC-3 异种移植瘤的人源化 HuNOG-EXL 小鼠中均改善了肿瘤抑制。总之，这些结果支持 BCA101 作为单药治疗以及与免疫检查点治疗联合的临床开发。意义：BCA101的双功能mAb融合设计将其靶向至肿瘤微环境，在该环境中抑制EGFR并中和TGFβ，从而诱导免疫激活并抑制肿瘤生长。
UNLABELLED: 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.
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