LBPO.ET01 · 实验与分子治疗 · Late-Breaking
BCG048：一种靶向ITGB6和B7H3的新型双特异性双载荷ADC，在患者来源肿瘤异种移植模型中展现出强效疗效
BCG048, a novel bispecific dual-payload ADC targeting ITGB6 and B7H3, exhibited potent efficacy in patient-derived tumor xenograft models
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摘要 Abstract
中文摘要
整合素alphavbeta6（ITGB6）是一种位于上皮细胞表面的异二聚体，在上皮-间质转化（EMT）过程中上调，并在多种实体瘤中过表达，与不良预后相关。B7H3（CD276）是B7家族免疫检查点分子的成员，也在多种癌症中过表达并与不利结局相关。除促进免疫逃逸外，B7H3还促进肿瘤生长、转移、治疗耐药和血管生成，使其成为一个重要的治疗靶点。ITGB6和B7H3目前均在进行抗体药物偶联物（ADC）疗法的开发，但尚无获批。值得注意的是，ITGB6和B7H3在多种实体瘤中共同过表达，包括头颈部鳞状细胞癌、食管癌、膀胱尿路上皮癌、胰腺腺癌和非小细胞肺癌（NSCLC）。我们使用RenLite小鼠平台开发了一种同时靶向ITGB6和B7H3的双特异性抗体（bsAb）。该bsAb对一组肿瘤细胞系表现出强结合，表明其在靶向过表达这两种蛋白的肿瘤方面具有潜在有效性。此外，该bsAb在ITGB6和B7H3表达水平不一的肿瘤细胞系中均表现出稳健结合。令人惊讶的是，无论表达水平如何，该bsAb在所有测试细胞系中还增强了其内化。这一发现表明该bsAb可能利用一种促进内化的机制，可能带来细胞毒性药物递送的改善。随后我们将该bsAb偶联至vcMMAE，该偶联物显示出强效的体内疗效。使用结合拓扑异构酶I抑制剂和微管抑制剂的双载荷策略对双特异性抗体（bsAb）进行偶联，从而开发出BCG048。与单载荷ADC相比，无论单独使用还是联合使用，这种创新化合物均展现出协同效应。BCG048在PDX模型中优于基准ADC。这些结果表明，BCG048有效应对靶点表达和肿瘤异质性，从而扩大了可从其使用中获益的患者群体。此外，BCG048有望克服原发耐药并延缓耐药的获得，最终增强在异质性肿瘤中的疗效。仍需进一步研究以评估其在临床前和临床环境中的疗效和安全性。
查看英文原文 English abstract
Integrin alphavbeta6 (ITGB6) is a heterodimer located on epithelial cell surfaces, upregulated during epithelial-mesenchymal transition (EMT), and overexpressed in various solid tumors, which is associated with poor prognosis. B7H3 (CD276), a member of the B7 family of immune checkpoint molecules, is also overexpressed in multiple cancers and is linked to unfavorable outcomes. In addition to facilitating immune evasion, B7H3 promotes tumor growth, metastasis, therapy resistance, and angiogenesis, making it a significant therapeutic target. Both ITGB6 and B7H3 are currently under development for antibody-drug conjugate (ADC) therapies, but none have been approved yet.Notably, ITGB6 and B7H3 are co-overexpressed in various solid tumors, including head and neck squamous cell carcinoma, esophageal carcinoma, bladder urothelial carcinoma, pancreatic adenocarcinoma, and non-small cell lung cancer (NSCLC). We developed a bispecific antibody (bsAb) targeting both ITGB6 and B7H3 using the RenLite mice platform. This bsAb demonstrated strong binding to a panel of tumor cell lines, suggesting its potential effectiveness in targeting tumors that overexpress these two proteins. Additionally, the bsAb demonstrated robust binding across tumor cell lines with varying levels of ITGB6 and B7H3 expression. Surprisingly, the bsAb also enhanced its internalization in all tested cell lines, regardless of their expression levels. This finding suggests that the bsAb may utilize a mechanism that promotes internalization, potentially leading to improved delivery of cytotoxic agents. Then we conjugated the bsAb to vcMMAE, and the conjugate showed potent in vivo efficacy. The conjugation of the bispecific antibody (bsAb) using a dual-payload strategy that combines a topoisomerase I inhibitor and a microtubule inhibitor has led to the development of BCG048. This innovative compound demonstrates a synergistic effect compared to single-payload ADCs, both when used alone and in combination. BCG048 outperforms benchmark ADCs in PDX models. These results indicate that BCG048 effectively addresses target expression and tumor heterogeneity, thereby expanding the population of patients who can benefit from its use. Additionally, BCG048 has the potential to overcome primary resistance and delay the acquisition of resistance, ultimately enhancing efficacy in heterogeneous tumors. Further studies will be necessary to evaluate its efficacy and safety in preclinical and clinical settings.
利益披露 Disclosure
B. Yang, None..
M. Li, None..
H. Liu, None..
C. Shang, None.