PO.IM01.13 · 免疫学
BCG044——一种靶向EpCAM和HER3、用于治疗结直肠癌及其他肿瘤的新型双特异性ADC的临床前研究
Preclinical study of BCG044, a novel bispecific ADC targeting EpCAM and HER3 for the treatment of colorectal and other tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
结直肠癌(CRC)是第三大最常见癌症，也是癌症相关死亡的第二大主因。遗憾的是，现有疗法对长期生存的疗效有限。抗体偶联药物(ADC)是一类新兴的治疗手段，在肿瘤学领域具有潜力，但迄今为止其在结直肠癌中的疗效有限。因此，鉴定新的药物靶点并开发ADC对改善治疗结局至关重要。上皮细胞黏附分子(EpCAM)是一种跨膜糖蛋白，广泛表达于多种癌症中，尤其是结直肠癌、胃癌、卵巢癌和肺癌。然而，其在正常组织中的存在导致既往生物治疗产生不良反应，包括与全身给药相关的胃肠道毒性和胰腺炎。
在本研究中，我们开发了一种创新方法，生成同时靶向EpCAM和HER3的双特异性ADC，HER3是另一种在多种实体瘤中广泛过表达的抗原，包括胃肠道癌、乳腺癌和NSCLC。通过采用"1+1"形式，我们旨在减轻EpCAM相关毒性，同时增强肿瘤选择性。BCG044双特异性抗体(bsAb)能有效结合多种胃肠道肿瘤细胞系。值得注意的是，EpCAM和HER3的单价形式导致肿瘤细胞内化减少。相反，bsAb同时结合两个靶点使内化最大化。这表明bsAb需要以双价方式靶向肿瘤细胞。当与新型TOP1抑制剂连接子-载荷BLD1102偶联时，BCG044在结直肠癌、乳腺癌和NSCLC的PDX模型中展现出与EpCAM基准ADC相当的强效疗效，并显示出强于HER3基准ADC的效果。随后，我们利用人源化EpCAM小鼠测试了一种含有相同EpCAM臂以及与小鼠HER3交叉反应的HER3臂的替代ADC。该替代ADC相较于亲本EpCAM ADC表现出更好的耐受性。总之，BCG044展现出在增强肿瘤选择性的同时维持对结直肠癌及其他实体瘤强效疗效的潜力。
查看英文原文 English abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths. Unfortunately, current therapies have limited effectiveness on long-term survival. Antibody-drug conjugates (ADCs) represent an emerging class of treatments with potential in oncology, but their efficacy in colorectal cancer has been limited thus far. Therefore, identifying new drug targets and developing ADCs are essential for improving treatment outcomes. Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein widely expressed in various cancers, notably colorectal, gastric, ovarian, and lung cancers. However, its presence in normal tissues has led to adverse effects from previous biologic therapies, including gastrointestinal toxicity and pancreatitis associated with systemic administration.
In this study, we developed an innovative approach to generate a bispecific ADC targeting both EpCAM and HER3, another antigen that is widely overexpressed in various solid tumors, including gastrointestinal cancers, breast cancer, and NSCLC. By employing a "1+1" format, we aimed to mitigate EpCAM-related toxicity while enhancing tumor selectivity. The BCG044 bispecific antibody (bsAb) effectively bound to a diverse range of gastrointestinal tumor cell lines. Notably, the monovalent form of EpCAM and HER3 resulted in decreased internalization within tumor cells. In contrast, simultaneous engagement of both targets by bsAbs maximized internalization. This suggests that bsAb requires targeting of tumor cells with bivalency. When conjugated with BLD1102, a novel TOP1 inhibitor linker-payload, BCG044 exhibited potent efficacy comparable to the EpCAM benchmark ADC and demonstrated stronger effects than the HER3 benchmark ADC in colorectal, breast, and NSCLC PDX models. Subsequently, we utilized humanized EpCAM mice to test a surrogate ADC that contained the same EpCAM arm, along with a HER3 arm that cross-reacted with mouse HER3. The surrogate ADC demonstrated better tolerance compared to both the parent EpCAM ADC. In summary, BCG044 exhibited the potential to enhance tumor selectivity while maintaining potent efficacy against colorectal and other solid tumors.
利益披露 Disclosure
J. Lee, None..
Z. Li, None..
C. Shang, None..
Y. Yang, None.