体内
细胞毒性T细胞
抗体-药物偶联物
抗体
医学
癌症研究
体外
单克隆抗体
药理学
免疫学
化学
生物
生物化学
生物技术
作者
Stéphanie Decary,Pierre‐François Berne,Céline Nicolazzi,Anne-Marie Lefebvre,Tarik Dabdoubi,Béatrice Cameron,Pierrick Rival,Catherine Devaud,Catherine Prades,Hervé Bouchard,Alhassan Cassé,Christophe Henry,Céline Amara,Claire Brillac,Paul Ferrari,Laetitia Maçon,Eric Lacoste,Cécile Combeau,Eric Beys,Souâd Naimi,Carlos García‐Echeverría,Jean‐François Mayaux,Véronique Blanc
标识
DOI:10.1158/1078-0432.ccr-19-4051
摘要
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein that has limited expression in normal adult tissues, but is overexpressed in carcinomas of the gastrointestinal tract, the genitourinary and respiratory systems, and breast cancer. As such, CEACAM5 is an attractive target for antibody-based therapies designed to selectively deliver cytotoxic drugs to certain epithelial tumors. Here, we describe preclinical data for a novel antibody-drug conjugate (ADC), SAR408701, which consists of an anti-CEACAM5 antibody (SAR408377) coupled to a maytansinoid agent DM4 via a cleavable linker.The specificity and binding affinity of SAR408701 to human and cynomolgus monkey CEACAM5 were tested in vitro. The cytotoxic activity of SAR408701 was assessed in CEACAM5-expressing tumor cell lines and using patient-derived xenograft mouse models of CEACAM5-positive tumors. Pharmacokinetic-pharmacodynamic and pharmacokinetic-efficacy relationships were established. SAR408701 toxicity was evaluated in cynomolgus monkey.SAR408701 bound selectively to human and cynomolgus monkey CEACAM5 with similar apparent Kd values (0.017 nmol/L and 0.024 nmol/L, respectively). Both in vitro and in vivo evaluations showed that SAR408701 has cytotoxic activity, leading to in vivo efficacy in single and repeated dosing. Single doses of SAR408701 induced significant increases in the tumor expression of phosphorylated histone H3, confirming the tubulin-targeting mechanism of action. The overall toxicity profile of SAR408701 in cynomolgus monkey was similar to that observed after intravenous administration of DM4 alone.On the basis of these preclinical data, the ADC SAR408701 is a promising candidate for development as a potential treatment for patients with CEACAM5-positive tumors.
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