A Novel Anti-Ceacam5 Maytansinoid-Antibody-Drug Conjugate For The Treatment Of Colorectal, Lung And Gastric Tumors

Carcinoembryonic antigen cell adhesion molecule 5, CEACAM5 (CEA, CD66e) is a well known tumor marker, in particular in colorectal carcinomas, where circulating CEA is used to monitor response to chemotherapy. This GPI anchored glycoprotein belongs to the CEA-related cell adhesion molecule (CEACAM) family and shares domains identity to other members, like CEACAM6. CEACAM5 is expressed in non-human primate and also shares identity to different members, making it difficult to find an antibody both selective to human CEACAM5 and cross-reacting solely with monkey CEACAM5. CEACAM5 has been described in the literature as a poorly internalizing surface protein, but interestingly, antibodies with different uptake capacities have been found. CEACAM5 is highly expressed at the surface of tumor cells in several epithelial tumors, including CRC, lung and gastric tumors and displays a limited expression in normal tissue where it is found solely at the luminal surface of columnar absorptive cells. This prompted us to develop an anti-CEACAM5 antibody-drug conjugate (ADC) for the treatment of CEACAM5-positive tumors. We generated multiple anti-CEACAM5 antibodies by immunization of Balb/c mice with recombinant human and monkey CEACAM5 extracellular domain and CEACAM5-positive tumor cells. We selected a highly specific CEACAM5 antibody that cross-reacts with monkey. The Alexa488-labeled anti CEACAM5 antibody internalizes in tumor cells and is processed in lysosomes leading to free Alexa488 molecules. Although the internalization rate was shown to be moderate, the high number of CEACAM5 at the surface of tumor cells allowed to produce a high number of free Alexa488, suggesting that the antibody could be suited for conjugation to a cytotoxic molecule. Indeed, conjugation of the antibody to the cytotoxic maytansinoid, DM4, with the cleavable SPDB linker generated SAR408701, which kills different CEACAM5-positive tumor cells at sub-nM concentration. SAR408701 in vivo efficacy was evaluated in CRC, lung and gastric patient-derived xenografts (PDXs), following a single injection of ADC at low doses (2.5-5 mg/kg). The conjugate was able to elicit strong and specific antitumor efficacy in a number of PDX models representative of the CEACAM5-positive patient population. Repeating the administrations resulted in most cases in a more pronounced antitumor efficacy even at doses that were otherwise marginally active as single dose. SAR408701 was well tolerated in cynomologus monkey and displayed similar toxicity profile as other SPDB-DM4 ADCs. Based on preclinical efficacy data and the absence of target mediated toxicity in monkey, SAR408701 is expected to have anticancer activity with a favorable therapeutic index, warranting its evaluation in patients with CEACAM5-positive tumors. Citation Format: Stephanie Decary, Pierre-Francois Berne, Celine Nicolazzi, Anne-Marie Lefebvre, Tarik Dabdoubi, Beatrice Cameron, Catherine Devaud, Catherine Prades, Herve Bouchard, Alhassan Casse, Christophe Henry, Celine Amara, Paul Ferrari, Laetitia Macon, Eric Lacoste, Cecile Combeau, Eric Beys, Souad Naimi, Francis Blanche, Carlos Garcia-Echeverria, Jean-Francois Mayaux, Veronique Blanc. A novel anti-CEACAM5 maytansinoid-antibody-drug conjugate for the treatment of colorectal, lung and gastric tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1688. doi:10.1158/1538-7445.AM2015-1688