RemeGen, Ltd., Yantai, 264006, Shandong, China.
Mabplex International Ltd., Yantai, 264006, Shandong, China.
Target Oncol. 2019 Feb;14(1):93-105. doi: 10.1007/s11523-018-0616-8.
Overexpression of epidermal growth factor receptor (EGFR) is common in pancreatic cancer and associated with the poor prognosis of this malignancy.
To develop anti-EGFR antibody-drug conjugates (ADCs) for use in a novel EGFR-targeting approach to treat pancreatic cancer.
A humanized anti-EGFR monoclonal antibody (RC68) was generated by mouse immunization and complementary-determining region grafting technology. Two RC68-based ADCs, RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE, were synthesized by conjugating monomethyl auristatin E (MMAE), a small-molecule cytotoxin, to RC68 through two distinct linkers (MC and PY). Internalization of the RC68-based ADCs was examined by flow cytometry. The in vitro and in vivo antitumor activities of RC68-based ADCs were evaluated in human pancreatic cancer cells and in a BXPC-3 xenograft nude mouse model, respectively.
The RC68-based ADCs bound to EGFR on the surface of tumor cells and were effectively internalized, resulting in the death of EGFR-positive cancer cell lines. The RC68-based ADCs (at 5 or 10 mg/kg) were more potent than gemcitabine hydrochloride (60 mg/kg) at inhibiting the growth of BXPC-3 xenografts. Moreover, RC68-PY-VC-PAB-MMAE was found to have superior stability in human plasma compared with RC68-MC-VC-PAB-MMAE.
A novel EGFR-targeting ADC, RC68-PY-VC-PAB-MMAE, shows promise as an effective, selective, and safe therapeutic agent for EGFR-positive pancreatic cancer.
表皮生长因子受体（EGFR）在胰腺癌中过度表达，与这种恶性肿瘤的不良预后相关。
开发针对 EGFR 的抗体药物偶联物（ADC），用于治疗胰腺癌的新型 EGFR 靶向方法。
通过小鼠免疫和互补决定区移植技术生成了一种人源化抗 EGFR 单克隆抗体（RC68）。通过将小分子细胞毒素单甲基澳瑞他汀 E（MMAE）通过两种不同的接头（MC 和 PY）与 RC68 缀合，合成了两种基于 RC68 的 ADC，RC68-MC-VC-PAB-MMAE 和 RC68-PY-VC-PAB-MMAE。通过流式细胞术检查 RC68 基 ADC 的内化情况。分别在人胰腺癌细胞和 BXPC-3 异种移植裸鼠模型中评估了 RC68 基 ADC 的体外和体内抗肿瘤活性。
RC68 基 ADC 与肿瘤细胞表面的 EGFR 结合，并被有效内化，导致 EGFR 阳性癌细胞系死亡。RC68 基 ADC（5 或 10 mg/kg）比盐酸吉西他滨（60 mg/kg）更能抑制 BXPC-3 异种移植的生长。此外，与 RC68-MC-VC-PAB-MMAE 相比，RC68-PY-VC-PAB-MMAE 在人血浆中具有更好的稳定性。
新型 EGFR 靶向 ADC，RC68-PY-VC-PAB-MMAE，作为一种有效的、选择性的、安全的针对 EGFR 阳性胰腺癌的治疗药物具有很大的潜力。
