PO.ET02.04 · 实验与分子治疗
BCG040，一种新型靶向B7-H4的双互补位ADC，在异质性肿瘤中展现出更优的临床前疗效
BCG040, a novel B7-H4-targeting biparatopic ADC, demonstrates superior preclinical efficacy in heterogeneous tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
B7-H4（VTCN1）在许多上皮恶性肿瘤中过表达，尤其是在卵巢癌、乳腺癌、胆道癌和胰腺癌中。这些肿瘤因其侵袭性强和预后不良，往往对化疗和免疫治疗均耐药。在此，我们介绍BCG040，一种新型首创的、全人源IgG1κ双互补位B7-H4 ADC。BCG040结合两个不重叠的B7-H4表位，并通过一种亲水性蛋白酶可裂解连接子偶联强效的拓扑异构酶I（TOP1）抑制剂BCPT02（DAR≈8）。在体外，BCG040对B7-H4表现出纳摩尔级亲和力，优于Hu2F7和SGN-B7H4V基准类似物，具有完全的人/食蟹猴交叉反应性，且与其他B7家族成员无脱靶结合。BCG040在乳腺癌和卵巢癌细胞中表现出比两种类似物更强的结合和更快的内化。在体内，单次低剂量的BCG040在乳腺癌PDX模型中显示出持久的肿瘤消退（约40天），并在胰腺癌PDX模型中显示出显著疗效，优于其他ADC，如Hu2F7、SGN-B7H4V或FPA150（偶联MMAE或BCPT02）。这种强效疗效在无可观察毒性的情况下实现，并得到良好的药代动力学（PK）特征的支持。此外，该药物展现出优异的可开发性。BCG040增强的治疗活性归因于其独特的双互补位设计，该设计促进受体聚集和加速的胞内转运，从而增强载荷递送。值得注意的是，含BCPT02的ADC在异质性PDX肿瘤中展现出强效的抗肿瘤活性，而基于MMAE的偶联物则无效。这些发现凸显了BCG040作为一种有前景的治疗候选药物用于治疗胰腺癌、胆道癌、卵巢癌和乳腺癌的潜力。
查看英文原文 English abstract
B7-H4 (VTCN1) is overexpressed in many epithelial malignancies, particularly in ovarian, breast, biliary tract, and pancreatic cancers. These tumors are often resistant to both chemotherapy and immunotherapy, due to their aggressive nature and poor prognosis. Here, we present BCG040, a novel first-in-class, fully human IgG1κ biparatopic B7-H4 ADC. BCG040 binds to two non-overlapping B7-H4 epitopes and is conjugated to the potent topoisomerase I (TOP1) inhibitor BCPT02 (DAR≈8) via a hydrophilic protease-cleavable linker. In vitro , BCG040 showed nanomolar affinity for B7-H4, superior to Hu2F7 and SGN-B7H4V benchmark analogs, with fully human/cynomolgus cross-reactivity and no off-target binding to other B7 family members. BCG040 exhibited stronger binding and more rapid internalization than the two analogs in breast and ovarian cancer cells. In vivo , a single low dose of BCG040 showed durable tumor regressions (~40 days) in breast cancer PDX models and significant efficacy in pancreatic cancer PDX models, outperforming other ADCs such as Hu2F7, SGN-B7H4V, or FPA150 (conjugated with MMAE or BCPT02). This potent efficacy was achieved without observable toxicity and was supported by a favorable pharmacokinetic (PK) profile. Furthermore, this drug demonstrates excellent developability. The enhanced therapeutic activity of BCG040 is attributed to its unique biparatopic design, which promotes receptor clustering and accelerated intracellular trafficking, leading to enhanced delivery of payload. Notably, BCPT02-containing ADCs exhibited potent antitumor activity in heterogeneous PDX tumors, whereas MMAE-based conjugates were ineffective. These findings underscore the potential of BCG040 as a promising therapeutic candidate for the treatment of pancreatic, biliary tract, ovarian, and breast cancers.
利益披露 Disclosure
G. Wang, None..
P. Li, None..
Y. Zhu, None..
Y. Guo, None.