A Genetically Encoded Endogenous Antibody Recruitment Strategy for Innate Immune-Mediated Killing of Cancer Cells

Antibody-recruiting molecules (ARMs) are bivalent molecules that contain a cell-binding domain and an antibody-binding domain. ARMs are designed to redirect circulating endogenous antibodies from the bloodstream to the surface of cancer cells and thereby trigger innate immune-mediated killing of the latter. The current generation of clinically explored ARMs relies on synthetic small molecule haptens. However, their effectiveness is restricted by the low affinity of the available repertoire of endogenous anti-hapten antibodies. Utilizing endogenous high-affinity allergen-specific antibodies could potentially circumvent this issue. In this study, a genetically encoded antibody-recruiting strategy that utilizes lipid nanoparticles (LNPs) to deliver mRNA encoding the house dust mite allergen Der p 2, fused to a cell membrane anchor, to induce cell surface display and enable the recruitment of anti-Der p 2 antibodies, is presented. Der p 2 mRNA LNP-treated cancer cells cause greatly reduced pulmonary tumor burden in Der p 2 immunized mice, compared to untreated cells or nonimmunized mice. Reduced tumor growth is dependent on circulating antibodies, and neutrophils are identified as a key immune cell subset recognizing and eliminating Der p 2-displaying cancer cells. These findings emphasize the effectiveness of mRNA LNPs as a powerful tool for generating a genetically encoded ARM strategy, with potential applications in cancer immunotherapy.