Abstract 2736: Ligand-independent targeting of tumor cells for antibody-dependent cell-mediated cytotoxicity

Abstract Introduction: Biological targeting is a key concept in cancer treatment utilized by most therapeutics. Targeted agents that selectively treat diseased tissues while reducing off-target effects to normal tissues are widely used for cancer therapies. However, key hurdles include: (i) a limited number of tumor-specific biomarkers expressed in sufficiently high levels for targeted therapy, (ii) lack of specific biomarkers amenable to targeting, and (iii) current technologies rely on largely protein-based targeting ligands limiting the applications of these therapies due to final conjugates with low payloads. We developed a novel method for tumor-specific delivery by combining metabolic glycoengineering and nanomedicine to engineer targetable chemical groups on cancer cells and enable directed treatments. We hypothesize that increased Fc fragments on the surface of tumor cells can enable antibody-dependent cell mediated cytotoxicity (ADCC) response to tumor cells, providing innate immunotherapy. Materials/Methods: We formulated nanoparticles (NPs) using polyethylene glycol-ply lactic acid-co-glycolic acid (PEG-PLGA). Using the Dolomite microfluidic device, we formed NPs by nanoprecipitation of PEG-PLGA with tetraacetylated N-azidoacetyl-D-mannosamine (Ac4ManNAz), a sialic acid analogue containing a click chemistry group. We targeted this reactive group by functionalizing the Fc fragment with dibenzylcyclooctyne (DBCO). We characterized the NPs using dynamic light scattering (DLS), charge measurements and transmission electron microscopy (TEM). We evaluated toxicity using a cell viability assay and assessed preliminary efficacy with a tumor growth delay study. Results: NP characterization revealed a size of 30-40 nm via DLS, congruent with TEM imaging. Charge measurements ranged from -4 to +4 mV. Toxicity studies revealed no differences in cell viability amongst different treatment groups. Preliminary efficacy studies demonstrated improved tumor growth delay in the cohort of mice treated with a combination of NPs and Fc-DBCO conjugate, as well as a survival benefit. Median OS was 31. 5 days for the control groups vs 57. 5 days for the combination treated group (p = 0. 0067). Conclusion: There is growing interest in harnessing the power of the innate immune response to shape anti-tumor immunity. This is because clinical data demonstrates tumor cells can evade the adaptive immune system through mutations as well as downregulate MHC receptors. One of the most effective innate immune responses is ADCC. To this end, we developed a novel method for tumor-specific delivery of Fc fragments to enhance ADCC. While this data reveals improved tumor growth delay and a survival benefit, the sample size is limited, and a larger study is needed to evaluate the potential benefits of this strategy. Furthermore, correlative studies are needed to identify the mechanism for treatment response. Citation Format: Maureen L. Aliru, Nikhila R. Sultanpuram, Kin Man Au, Tian Zhang, Andrew Z. Wang. Ligand-independent targeting of tumor cells for antibody-dependent cell-mediated cytotoxicity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2736.