LBPO.IM03 · 免疫学 · Late-Breaking
BCG047：一种靶向FOLR1的新型重链抗体偶联药物，展现出卓越的临床前抗肿瘤疗效
BCG047, a novel heavy chain antibody-drug conjugate targeting FOLR1, demonstrates outstanding preclinical antitumor efficacy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
叶酸受体1（FOLR1）是一种GPI锚定受体，对叶酸转运至关重要。它在正常组织中表达较低，但在肿瘤中大量表达，尤其是卵巢癌，使其成为重要的治疗靶点。Elahere是一种靶向FRalpha的ADC，可改善铂耐药卵巢癌的无进展生存期，但其应用局限于FRalpha高表达的患者，并存在安全性问题。这凸显了对新一代FRalpha靶向ADC的需求，此类ADC应能够治疗FOLR1水平各异的患者并采用更安全的替代方案。通过利用我们的全人源RenNano®小鼠，我们鉴定出一种抗FOLR1的VHH——HCAb-01，与基准抗体相比，它识别一个独特的FOLR1表位。研究表明其可特异性结合人源和猴源FOLR1抗原，而不识别FOLR家族的其他成员。HCAb-01对不同表达水平的FOLR1肿瘤细胞均表现出强结合亲和力，提示其具有有效靶向不同FOLR1表达水平细胞的潜力。此外，HCAb-01在肿瘤细胞中展现出高效的内化。HCAb-01具有良好的理化性质，并在应激条件下保持一致的结合活性。此外，HCAb-01在C57BL/6小鼠中表现出可接受的药代动力学（PK）。随后，我们将HCAb-01与BLD1102（一种基于拓扑异构酶I抑制剂（TOP1i）的接头-载荷）偶联，生成重链抗体偶联药物（HcADC）BCG047。BCG047在PDX模型中展现出强效疗效，尤其是在FOLR1低表达模型中，优于基准ADC。这些数据提示BCG047是一种有前景的靶向FOLR1的治疗策略，有望扩大从该治疗中获益的患者群体，尤其是在FOLR1低表达的情况下。为增强药代动力学并提高疗效，目前正在对BCG047进行旨在实现半衰期延长的改造，以推进进一步的临床前开发。
查看英文原文 English abstract
Folate receptor 1 (FOLR1) is a GPI-anchored receptor crucial for folate transport. It has low expression in normal tissues but is abundant in tumors, especially ovarian cancers, making it an important therapeutic target. Elahere, an FRalpha-targeted ADC, improves progression-free survival in platinum-resistant ovarian cancer but is limited to patients with high FRalpha expression and poses safety concerns. This highlights the need for next-generation FRalpha-targeted ADCs that can treat patients with varying FOLR1 levels and use safer alternatives. By utilizing our fully human RenNano ® mice, we identified an anti-FOLR1 VHH, HCAb-01, which recognizes a distinct FOLR1 epitope compared to the benchmark antibodies. It was shown to bind specifically to both human and monkey FOLR1 antigens, without recognizing other members of the FOLR family. HCAb-01 displayed a strong binding affinity for FOLR1 tumor cells with varying expression levels, suggesting its potential for effectively targeting cells with different levels of FOLR1 expression. Additionally, HCAb-01 demonstrated efficient internalization in tumor cells. HCAb-01 displayed favorable physicochemical properties and maintained consistent binding activity under stress conditions. Additionally, HCAb-01 demonstrated acceptable pharmacokinetics (PK) in C57BL/6 mice. We then conjugated HCAb-01 to BLD1102, a topoisomerase I inhibitor (TOP1i) based linker-payload, to generate a heavy-chain antibody-drug conjugate (HcADC), BCG047. BCG047 demonstrated potent efficacy in PDX models, particularly in an FOLR1-low model, outperforming the benchmark ADC. These data suggest that BCG047 is a promising therapeutic strategy targeting FOLR1, with the potential to expand the patient population benefiting from this treatment, particularly in low FOLR1 expression settings. To enhance pharmacokinetics and improve efficacy, modifications to BCG047 aimed at achieving a prolonged half-life are currently underway for further preclinical development.
利益披露 Disclosure
B. Yang, None..
Y. Zhang, None..
Y. Xu, None..
C. Shang, None.