PO.ET02.02 · 实验与分子治疗
SCR-A014，一种靶向B7H3和DLL3用于SCLC治疗的新型双特异性ADC，展现出强效的抗肿瘤疗效
SCR-A014, a novel bispecific ADC targeting B7H3 and DLL3 for SCLC therapy, exhibits potent anti-tumor efficacy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：小细胞肺癌（SCLC）是最具侵袭性的肺神经内分泌肿瘤，约占所有肺癌的15%。Delta样配体3（DLL3）是一种抑制性Notch配体，在SCLC和其他神经内分泌肿瘤中高表达，但在正常组织中表达极少。B7H3，又称CD276，是一种属于B7家族的I型跨膜蛋白，该家族包括PD-L1、B7-1和B7-2等免疫检查点分子。DLL3和B7H3在小细胞肺癌（SCLC）肿瘤组织中高度过表达，而在正常组织中存在有限，使它们成为有吸引力的治疗靶点。B7H3和DLL3两个靶点在SCLC患者样本中均显示出高阳性率（>80%）。然而，DLL3和B7H3的表达水平并不高，大多数样本处于1+水平。此外，B7H3表现出相对缓慢的内化，而DLL3表现出快速内化。基于这些互补特性，我们提出了一种同时靶向B7H3和DLL3的双抗体药物偶联策略。这一创新方法旨在增强抗肿瘤疗效。
方法与结果：我们开发了一种名为SCR-A014的新型B7H3 x DLL3靶向双特异性抗体药物偶联物（ADC），其由B7H3/DLL3双特异性抗体偶联拓扑异构酶1抑制剂（CPT116）组成。SCR-A014以高亲和力特异性结合B7H3和DLL3，并在B7H3/DLL3共表达细胞系中相较于亲本单克隆抗体ADC分别表现出增强的内化和结合能力。SCR-A014在多种肿瘤细胞系中诱导肿瘤细胞裂解，并在多个CDX模型中以剂量依赖方式显示出显著的抗肿瘤疗效。在B7H3+DLL3+双阳性肿瘤细胞中，SCR-A014表现出显著强于其亲本单克隆ADC或临床ADC的抗肿瘤活性。SCR-A014还具有很好的稳定性和良好的可开发性。
结论：这些发现表明SCR-A014是一种潜在的首创双特异性ADC，可能为B7H3和DLL3阳性的SCLC癌症提供一种新型治疗策略。
查看英文原文 English abstract
Background: Small cell lung cancer (SCLC) is a most aggressive lung neuroendocrine tumor, accounting for approximately 15% of all lung cancers. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors but minimally expressed in normal tissues. B7H3, also known as CD276, is a type I transmembrane protein belonging to the B7 family that includes immune checkpoint molecules such as PD-L1, B7-1, and B7-2. DLL3 and B7H3 are highly overexpressed in small cell lung cancer (SCLC) tumor tissues, with limited presence in normal tissues, making them attractive therapeutic targets. Both B7H3 and DLL3 target shows a high positivity rate (>80%) in SCLC patient samples. However, the expression levels of DLL3 and B7H3 are not high, most samples are at a 1+ level. Moreover, B7H3 exhibits relatively slow internalization, whereas DLL3 demonstrates rapid internalization. Based on these complementary characteristics, we propose a dual-antibody drug conjugate strategy targeting both B7H3 and DLL3. This innovative approach aims to enhance antitumor efficacy.
Methods & Results: We developed a novel B7H3 x DLL3 targeted bispecific antibody-drug conjugate (ADC) called SCR-A014, which is comprised of B7H3/DLL3 bispecific antibody conjugated with topoisomerase 1 inhibitor (CPT116). SCR-A014 specifically bind B7H3 and DLL3 with high affinity, and showed enhanced internalization and binding capacity compared to parental monoclonal antibody ADC separately in the B7H3/DLL3 co-expressing cell line. SCR-A014 induced tumor cell lysis in various tumor cell lines, and showed remarkable anti-tumor efficacy in several CDX models in a dose dependent manner. SCR-A014 exhibits significantly stronger anti-tumor activity than their parental monoclonal-ADC or clinical ADC in B7H3+DLL3+ double positive tumor cells. SCR-A014 also have very good stability and favorable developability.
Conclusion: These findings suggest that SCR-A014 is a potential first-in-class bispecific ADC and may offer a novel therapeutic strategy for SCLC cancers positive for B7H3 and DLL3.
利益披露 Disclosure
G. Cheng, None..
Y. Fu, None..
J. Wang, None..
S. Wang, None..
G. Yang, None..
C. Xia, None..
X. Huang, None..
R. Tang, None.