Preclinical Activity of SAR408701: A Novel Anti-CEACAM5–maytansinoid Antibody–drug Conjugate for the Treatment of CEACAM5-positive Epithelial Tumors

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.

Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody–drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study

“…Carcinoembryonic antigen (CEA)-related cell adhesion molecule 5 (CEACAM5, also known as CD66e), a cell surface glycoprotein, is weakly expressed in normal epithelial tissues including colon, esophagus, head and neck, stomach, and cervix tissue but is highly expressed in several tumor types including gastrointestinal, lung, and breast. 1,2 In normal tissue, CEA protects luminal organs from microbial invasion. In tumor cells, CEACAM5 plays a contactmediating role during metastasis 3 and facilitates tumor invasion and metastasis.…”

“…9 Tusamitamab ravtansine has antitumor activity in CEACAM5-expressing tumor cell lines and patient-derived xenograft models. 2 Building on these promising preclinical results, a model-based approach was used to select potential phase I dosing regimens, which informed the design of the present first-in-human study. 6 Here we describe the safety, pharmacokinetics (PK), preliminary antitumor activity, and the maximum tolerated dose (MTD) of tusamitamab ravtansine.…”

A comprehensive review on antibody-drug conjugates (ADCs) in the treatment landscape of non-small cell lung cancer (NSCLC)

“…SAR408701 is a novel ADC that couples anti-CEACAM5 monoclonal antibody to the microtubule destabilizing agent maytansinoid DM4 [101]. First-in-human study of SAR408701 in CEACAM5-expression non-squamous NSCLC in 92 patients (28 moderate IHC expression and 64 high) showed ORR of 7.1% and 20.3% in moderate and high expressors respectively.…”

Antibody-Drug Conjugates and Tissue-Agnostic Drug Development

“…Both in vitro and in vivo evaluations showed that SAR408701, an ADC targeting CEACAM-5, has cytotoxic activity. 60…”