Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Drug-conjugates are an emerging class of anticancer agents combining the cytotoxic activity of highly potent chemotherapeutic agents with the target specificity of an antibody, a small molecule or a peptide ligand directed against a cancer-associated protein. With nearly half a century of development, profound advancements have been made in the development of these therapeutics. The most advanced are antibody-drug conjugates (ADCs) with currently &gt;100 in development and 11 approved by the FDA. To facilitate preclinical evaluation of novel drug conjugates, Reaction Biology and 4HF Biotec have developed a dedicated platform allowing specific in vitro and in silico analyses for this class of therapeutics. The platform is intended to provide information on the potency of the drug conjugate over the corresponding stand-alone cytotoxin, the cancer entities to be treated, the target engagement and the determinant(s) of cancer cell sensitivity. Here, we present our platform to refine antitumor potential of Sacituzumab govitecan (ScG), a recently approved TROP-2 targeted ADC used for the treatment of triple-negative breast cancer. First, we used the ProLiFiler™ (Reaction Biology), a cell proliferation and survival assay with 140 human cancer cell lines, to establish the antitumor profile of ScG, its payload SN-38 and three other cytotoxins (camptothecin, MMAE and mertansine) to validate the results of our assay. The IC50 obtained for the cytotoxins were next validated using the MoAFinder (4HF Biotec), a tool derived from the NIH COMPARE algorithm that ranks drugs based on the similarity of their growth inhibitory profiles. The analysis confirmed that SN-38 and camptothecin antitumor profiles, as established with the ProLiFiler, correlated best with other topoisomerase-1 inhibitors from our database of more than 1,000 compounds. Mertansine and MMAE correlated best with tubulin inhibitors and were more potent than camptothecin and SN-38. Overall, the response to these cytotoxins was stronger in cell lines from hyperproliferative cancers such as hematological malignancies than in those from solid cancers. Next, by using OMICS data (internal and publicly available), qPCR and flow cytometry connected to drug sensitivity profiles, we will present a differential biomarker screen of ScG vs. SN-38 to identify molecular determinants of sensitivity toward the ADC and its cytotoxin. We will address the expression level of TROP2 and its predictivity for tumor cell sensitivity, screen for predictors of SN-38 response and investigate possible off-target effects in cell lines sensitive to ScG but lacking TROP2 expression. Overall, the study demonstrates the potential of our platform to investigate drug conjugates. The comparative profiling of ScG and its payload allows to identify candidate cancer entities for ScG treatment and to improve patient enrollment into clinical trials using biomarkers.</jats:p>
<jats:p>Citation Format: Vincent Vuaroqueaux, Nadine Obier, Anne-Lise Peille, Daniel Feger, Katharina Schaich, Thomas Metz, Sebastian Dempe, Heinz-Herbert Fiebig, Jan Erik Ehlert. Introduction of a platform for preclinical profiling of drug conjugates: a case study with sacituzumab govitecan. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4895.</jats:p>