PO.IM01.13 · 免疫学
BCG018——一种靶向ITGB6并搭载拓扑异构酶I抑制剂载荷的ADC，在PDX模型中被证实具有临床前疗效
Preclinical efficacy of BCG018, an ADC targeting ITGB6 and incorporating a topoisomerase I inhibitor payload, was demonstrated to be effective in PDX models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
整合素alphavbeta6是由alphav和beta6亚基组成的异二聚体，主要存在于上皮细胞表面，已知在上皮-间质转化(EMT)过程中上调。其在多种实体瘤中过表达，并与患者预后不良相关，使其成为ADC治疗的一个有前景的靶点。然而，整合素家族体积庞大且结构复杂，给特异性抗体的开发带来了重大挑战。
在我们的研究中，我们鉴定出anti-ITGB6-B抗体，其相较于其他beta整合素能选择性结合ITGB6。这种特异性是利用全人源共同轻链RenLite小鼠(ITGB6敲除)确立的。经SPR和ELISA实验证实，anti-ITGB6-B抗体对ITGB6及其异二聚体alphavbeta6均表现出良好的结合亲和力，优于基准对照。
此外，anti-ITGB6-B在多种肿瘤细胞系中表现出优异的结合特性，能有效靶向不同ITGB6表达水平的细胞。重要的是，其内化活性被发现与基准对照相当或更强，增强了其治疗应用潜力。值得注意的是，在ELISA实验中anti-ITGB6-B并未阻断ITGB6与其配体LAP的相互作用，表明其有潜力作为一种不干扰关键信号通路的靶向疗法。anti-ITGB6-B还表现出优异的理化性质和可开发性，使其成为ADC治疗进一步开发的有前景候选者。
随后将anti-ITGB6-B与vcMMAE偶联。所得偶联物在PDX模型中展现出优于基准ADC的疗效，且不受ITGB6表达水平影响。此外，由anti-ITGB6-B与新型拓扑异构酶I抑制剂(BLD1102)偶联而成的BCG018，在胰腺癌、结直肠癌及NSCLC的PDX或CDX异种移植模型中显示出优于基准ADC的疗效。
总体而言，BCG018偶联物为靶向实体瘤中的整合素alphavbeta6提供了一种具有特异性和强效性的有前景策略。
查看英文原文 English abstract
Integrin alphavbeta6 is a heterodimer composed of alphav and beta6 subunits that is primarily found on the surfaces of epithelial cells and is known to be upregulated during the epithelial-mesenchymal transition (EMT). Its overexpression in various solid tumors, which correlates with poor patient prognosis, makes it a promising target for ADC therapy. However, the large size and complexity of the integrin family present significant challenges in developing specific antibodies.
In our studies, we identified the anti-ITGB6-B antibody, which selectively binds to ITGB6 over other beta integrins. This specificity was established using fully human common light chain RenLite mice with ITGB6 knockout. The anti-ITGB6-B antibody demonstrated good binding affinity for both ITGB6 and its heterodimer alphavbeta6, outperforming the benchmark, as confirmed by SPR and ELISA experiments.
Furthermore, anti-ITGB6-B exhibited excellent binding characteristics across multiple tumor cell lines, effectively targeting cells with varying levels of ITGB6 expression. Importantly, its internalization activity was found to be comparable to or greater than that of the benchmark, enhancing its potential for therapeutic applications. Notably, the anti-ITGB6-B did not block the interaction of ITGB6 with its ligand LAP in ELISA assays, indicating its potential as a targeted therapy without disrupting critical signaling pathways. The anti-ITGB6-B also exhibited excellent physicochemical properties and developability, making it a promising candidate for further development in ADC therapy.
The anti-ITGB6-B was then conjugated to vcMMAE. The resulting conjugate demonstrated superior efficacy to that of the benchmark ADC in PDX models, regardless of ITGB6 expression levels. Additionally, the BCG018, which is anti-ITGB6-B conjugated with a novel topoisomerase I inhibitor (BLD1102), showed superior efficacy to benchmark ADC in models of pancreatic, colorectal, and NSCLC PDX or CDX xenografts.
Overall, BCG018 conjugates offer a promising strategy for targeting integrin alphavbeta6 in solid tumors with specific and potent efficacy.
利益披露 Disclosure
Y. Yang, None..
M. Li, None..
C. Shang, None.