Abstract B145: PK/PD evaluation of an anti-CEACAM5 antibody drug conjugate, in a colon patient-derived-xenografted mice model

CEACAM5 is an oncofetal protein that is expressed in a number of tumors of epithelial origin such as colorectal cancer (CRC), lung and gastric cancer. Differential expression of CEACAM5 protein in tumor tissues compared to normal tissues make this target attractive for targeting with an antibody-drug conjugate (ADC). The ADC that is characterized in this study contains a specific anti-CEACAM5 antibody and the maytansinoid derivative DM4, a potent antimitotic agent that inhibits microtubule assembly. DM4 is covalently bound to the humanized IgG1 (hIgG) antibody through a N-succinimidyl-4-(2-pyridyldithio) butyrate (SPDB) linker that is stable in plasma and cleavable inside cells. After binding and internalization into CEACAM5-positive cancer cells, this ADC is degraded, releasing cytotoxic DM4 metabolites. In the present study the Pharmacokinetic (PK), Pharmacodynamic (PD) and efficacy relationships of this ADC were investigated against subcutaneous colon Patient-Derived-Xenograft (PDX) in severe combined immunodeficient (SCID) mice. The modulation of several biomarkers after a single administration of this compound at 3 dose levels were quantified in the tumor by immunoassay (phosphorylated Histone H3 (pHH3), a marker of cells arrested in mitosis and free human CEACAM5 expression). The spatial localization in the tumor of the biomarkers (pHH3, free human CEACAM5, DM4 and hIgG) was analyzed by immunohistochemistry (IHC). A population pharmacokinetic analysis of the ADC was performed first, followed by population PK/PD analysis for pHH3 induction and tumor growth inhibition (TGI). This study has shown both by immunoassay and IHC that a single administration of this anti-CEACAM5 ADC induced in the xenografted tumor a dose dependent increase of pHH3 expression compared to control, with a maximal induction observed at 24-48 hours. The levels of DM4 and hIgG detected by IHC in the tumor were dose dependent and progressively decreased with time. DM4 and hIgG part of the ADC were essentially immunodetected at the membrane level of tumor cells and sub-localization was observed in vesicular intracellular compartments at later time point which confirms ADC tumor cell penetration. The PK/PD relationship analysis indicated that compound concentration producing 50% of the maximum pHH3 stimulation was 2.3 μg/mL and the threshold concentration for tumor eradication was 8 μg/mL in this colon PDX model. Both immunoassay and IHC assessment confirmed that single administration of the ADC had no impact on CEACAM5 expression at the tumor cell membrane. Overall these data have confirmed mechanism of action of this anti-CEACAM5 ADC and its attractiveness as a potent compound to induce dose dependent CEACAM5 expressing tumor cell death. This compound is now being explored in a phase 1 clinical trial in cancer patients. Citation Format: Christophe Henry, Celine Nicolazzi, Celine Amara, Anne-Marie Lefebvre, Christelle Larois, Florence Attenot, Claire Brillac, Marion Bouillon-Pichault, Nathalie Fagniez, Stephanie Decary, Cecile Combeau, Pierre-Francois Berne, Souâd Naimi, Marielle Chiron, Veronique Blanc. PK/PD evaluation of an anti-CEACAM5 antibody drug conjugate, in a colon patient-derived-xenografted mice model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B145.