Program in Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
Oncology Group, Northern Biologics, Toronto, ON M5G 1L7, Canada.
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6812-6817. doi: 10.1073/pnas.1817246116. Epub 2019 Mar 20.
Aberrant activation of Wnt/β-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.
Wnt/β-连环蛋白信号通路的异常激活在癌症中经常发生。然而，由于 Wnt 在干细胞维持和组织动态平衡中的作用，该途径的治疗靶向变得复杂。在这里，我们评估了阻断 10 个人类 Wnt/Frizzled (FZD) 受体中的 6 个作为潜在治疗药物的抗体。晶体结构揭示了这些单克隆抗体 (mAb) 在 FZD 上的共同结合位点，阻断了与 Wnt 豆蔻酸部分的相互作用。然而，这些 mAb 在体内显示出胃肠道毒性或较差的血浆暴露。结构引导的工程用于改进每个 mAb 与 FZD 受体的结合，导致具有改善的体内耐受性和可开发性的抗体变体。重要的是，先导变体 mAb 显著抑制了 HPAF-II 胰腺肿瘤异种移植模型中的肿瘤生长。总之，我们的数据表明，具有广泛特异性的抗-FZD 癌症治疗抗体可以进行微调，以在体内暴露和耐受性的同时推动治疗效果。
