PO.ET02.02 · 实验与分子治疗
BCG041：一种靶向B7-H3和MUC1近膜区的首创双特异性ADC，具有优越的抗肿瘤活性
BCG041: A first-in-class bispecific ADC targeting B7-H3 and the proximal membrane region of MUC1 with superior antitumor activity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
BCG041是一种首创的全人源IgG1κ双特异性抗体药物偶联物（ADC），同时靶向B7-H3（CD276）和MUC1的近膜区。这两种肿瘤相关抗原在多种上皮性恶性肿瘤中广泛过表达，并各自与不良预后相关。其频繁的共表达为B7-H3和MUC1的双靶向提供了令人信服的理论依据。B7-H3 ADC（如ifinatamab deruxtecan，DS-7300）在治疗小细胞肺癌方面的有效性，即使在接受过大量既往治疗的患者中也是如此，凸显了该靶点的巨大潜力。另一方面，靶向MUC1的疗法历来遭遇若干障碍：糖型变异、SEA结构域裂解产生的可溶性MUC1诱饵，以及某些表位的内化不良。这些挑战可能限制治疗药物的递送并影响治疗指数。靶向MUC1的近膜区可降低脱落并增强内化，为克服这些挑战提供了可行的策略。基于该策略，BCG041采用亲水性、蛋白酶可裂解连接子和拓扑异构酶I抑制剂载荷（BCPT02，DAR≈8）开发，通过其两个靶点的亲合力驱动共接合来增强结合、内化和抗肿瘤效力。裸抗体表现出高亲和力，并与人和食蟹猴的B7-H3和MUC1完全交叉反应。在体外，BCG041在多种肿瘤细胞系中展现出比裸DS-7300或Gatipotuzumab类似物更强的结合和更快的内化。在体内，BCG041在多个肺癌和乳腺癌患者来源异种移植（PDX）模型中，相较于偶联至BCPT02或DXd的裸DS-7300或Gatipotuzumab的ADC，实现了优越的抗肿瘤疗效。治疗耐受性良好，未观察到体重下降或明显的全身毒性。药代动力学评估显示出良好的ADC特征，且该药物展现出优异的可开发性，CMC细胞系开发目前正在进行中。总之，这些数据将BCG041定位为一种极有前景的针对B7-H3/MUC1阳性恶性肿瘤的下一代双特异性ADC，可满足乳腺癌、肺癌、胃食管癌、头颈癌、结直肠癌、前列腺癌和卵巢癌方面重大的未满足临床需求。
查看英文原文 English abstract
BCG041 is a first-in-class fully human IgG1κ bispecific antibody-drug conjugate (ADC) targeting both B7-H3 (CD276) and the proximal membrane region of MUC1. These two tumor-associated antigens are broadly overexpressed in a wide range of epithelial malignancies and correlate with poor prognosis individually. The frequent co-expression provides a convincing rationale for dual targeting of B7-H3 and MUC1. The effectiveness of B7-H3 ADCs, such as ifinatamab deruxtecan (DS-7300), in treating small-cell lung cancer, even in patients who have received extensive prior treatment, emphasizes the significant potential of this target. On the other hand, therapies targeting MUC1 have historically encountered several obstacles: variations in glycoforms, the production of soluble MUC1 decoys due to SEA-domain cleavage, and the poor internalization of certain epitopes. These challenges can restrict the delivery of therapeutic agents and affect the therapeutic index. Targeting the proximal region of MUC1, which can decrease the shedding and enhance internalization, offers a feasible strategy to overcome these challenges. Based on this strategy, BCG041 was developed with a hydrophilic, protease-cleavable linker and a Topoisomerase-I inhibitor payload (BCPT02, DAR≈8) to enhance binding, internalization, and antitumor potency through the avidity-driven co-engagement of its two targets. The naked antibody exhibits high affinity and full cross-reactivity with both human and cynomolgus B7-H3 and MUC1. In vitro , BCG041 demonstrated stronger binding and faster internalization than naked DS-7300 or Gatipotuzumab analogs across multiple tumor cell lines. In vivo , BCG041 achieved superior antitumor efficacy compared to ADCs of naked DS-7300 or Gatipotuzumab conjugated to either BCPT02 or DXd in several patient-derived xenograft (PDX) models of lung and breast cancer. Treatment was well-tolerated, with no observed body-weight loss or overt systemic toxicity. Pharmacokinetic evaluation revealed a favorable ADC profile, and this drug demonstrates excellent developability, with CMC cell-line development currently ongoing. Together, these data position BCG041 as a highly promising next-generation bispecific ADC for B7-H3/MUC1-positive malignancies, addressing significant unmet clinical needs in breast, lung, gastro-esophageal, head-and-neck, colorectal, prostate, and ovarian cancers.
利益披露 Disclosure
I. Niu, None..
P. Li, None..
Y. Zhu, None..
Y. Guo, None.