121 Exploring therapeutic potential: insights from drug penetration and targeting using Nilogen’s ex-vivo 3D-EXpress tumoroid platform

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Background The effectiveness of therapeutics relies on their ability to penetrate and target solid tumors, often hindered by complex tumor-stroma architecture. Labeling therapeutics with fluorochromes aids in visualizing infiltration, binding, and internalization kinetics, enhancing our understanding of mechanisms of action for a given drug. Nilogen’s ex-vivo 3D-EXpress tumoroid platform retains the tumor microenvironment found in patient tumors, preserving the immune microenvironment and extracellular matrix (ECM); which allows for molecular exploration and novel target identification. Our labeling and imaging services, using this tumoroid platform, provide valuable insights into therapeutic efficacy and mechanism of action. Methods Using our 3D-EXpress tumoroid platform, we explored the efficacy of a Sacituzumab-Govitecan ADC (Antibody Drug Conjugates), labeled with fluorophores. The labeling used here can be conjugated covalently or non-covalently, across various functional modalities. Our established therapeutic labeling technique ensures the integrity of the therapeutic structure and binding domain availability without functional alteration. These labeling approaches facilitate the evaluation of therapeutic binding and internalization. Efficacy was assessed through functional assays-tumor cell killing and cytokine profiling. Results Using the 3D-EXpress tumoroid platform, we demonstrated the need for therapeutic labeling in ex-vivo assays to evaluate therapeutic efficacy. By labeling Govitecan, we were able to demonstrate the differences in kinetics between binding and internalization using the tumoroid platform. Labeled therapeutics were further used to study the mechanism of action and efficacy in tumoroids. Treatment with Govitecan resulted in increased tumor cell killing and induction of pro-inflammatory cytokine secretion compared to the isotype-treated controls. These findings confirmed there were no structural or conformational changes which might hinder the functional ability of the therapeutic due to the addition of the fluorescent labeling. Conclusions Drug penetration is crucial for effective delivery to target sites, especially within the tumor immune microenvironment of solid tumors. Poor penetration may prevent effective therapeutic intervention resulting in reduced drug efficacy. We are offering an optimized, low cost and time efficient therapeutic labeling option to gain valuable insights into therapeutic efficacy. This study depicts the use of therapeutic labeling to evaluate drug penetration and binding into solid tumor microenvironment. Ethics Approval Ethics approval was obtained through Chesapeak IRB (Pro00014313) which determined ‘Using the Department of Health and Human Services regulations at 45 CFR 46, the IRB determined that this research project does not constitute human subject research and, therefore, does not require IRB oversight.’ Full informed consent was obtained for each tissue used in this study.

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