PO.ET02.04 · 实验与分子治疗
一种用于治疗实体瘤的新型EGFR和B7H3双靶向抗体偶联药物（ADC）
A novel EGFR and B7H3 dual-targeted antibody-drug conjugate (ADC) for the treatment of solid tumors
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摘要 Abstract
中文摘要
背景：EGFR（又称HER1）是一种参与肿瘤进展的表皮生长因子受体，其在约70%的结直肠癌（CRC）、60%的肺癌以及超过90%的头颈部鳞状细胞癌（HNSCC）中过表达。B7H3属于B7免疫调节家族。B7H3在多种实体瘤中过表达，如肺癌、胃肠道癌和妇科肿瘤，但在正常组织中缺失或低表达。因此，同时靶向EGFR和B7H3可实现更好的治疗疗效。EGFR/B7H3-ADC是一类新型双特异性抗体偶联药物（ADC），由全人源抗EGFR/B7H3双特异性抗体（BsAb）通过可裂解连接子偶联TOP1i载荷组成。
方法：全人源单克隆抗体来源于转基因小鼠模型NeoMab小鼠。通过流式细胞术检测ADC与肿瘤细胞的结合。此外，我们使用偶联至ADC的pHrodo检测ADC在肿瘤细胞中的内化活性。采用CTG（CellTiter-Glo®）测定法测量细胞活力。在免疫缺陷小鼠中，构建异种移植模型以评估ADC的肿瘤生长抑制作用。
结果：EGFR/B7H3-ADC对肿瘤细胞的结合强于EGFR-ADC和B7H3-ADC。此外，EGFR/B7H3-ADC表现出更优的内化活性。更重要的是，我们的EGFR/B7H3-ADC在CDX小鼠模型中比EGFR-ADC和B7H3-ADC更有效地抑制肿瘤生长。
结论：我们的EGFR/B7H3-ADC在EGFR或B7H3阳性肿瘤患者中显示出潜在的治疗前景。本研究为支持我们新型双靶向抗体偶联药物（ADC）的进一步开发提供了关键依据。
查看英文原文 English abstract
Background: EGFR (also known as HER1) is an epidermal growth factor receptor involved in tumor progression, and its overexpression in approximately 70% of colorectal cancer (CRC), 60% of lung cancers, and over 90% of head and neck squamous cell carcinoma (HNSCC). B7H3 belongs to the B7 immunoregulatory family. B7H3 is overexpressed on a wide range of solid tumors such as lung cancers, gastrointestinal cancers and gynecological cancers, but its expression is absent or low in normal tissues. Therefore, dual targeting of both EGFR and B7H3 can achieve better therapeutical efficacy. EGFR/B7H3-ADCs are novel bispecific Antibody-drug Conjugates (ADCs), composed of fully human anti-EGFR/B7H3 bispecific antibodies (BsAbs) conjugated to TOP1i payload via cleavable linker.
Methods: the fully human monoclonal antibodies were derived from transgenic mouse model NeoMab mice. Flow cytometry was performed to examine binding of ADCs to tumor cells. In addition, we used pHrodo conjugated to ADCs to detect internalization activity in tumor cells. CTG (CellTiter-Glo®) assay was employed to measure cell viability. In immunodeficient mice, xenograft model was generated to assess the tumor growth inhibition of ADCs.
Results: EGFR/B7H3-ADCs showed stronger binding to tumor cells than EGFR-ADC and B7H3-ADC. Besides, EGFR/B7H3-ADCs displayed superior internalization activity. More importantly, our EGFR/B7H3-ADCs suppressed tumor growth more effectively than EGFR-ADC and B7H3-ADC in CDX mouse model.
Conclusion: our EGFR/B7H3-ADCs show potential therapeutic promise in patients with EGFR or B7H3 positive tumors. This study provides crucial rationale for supporting the further development of our novel dual-targeted Antibody-drug Conjugates (ADCs).
利益披露 Disclosure
M. Zhang, None..
X. Zhu, None..
J. Wang, None..
J. Zhao, None.