The Development of Chemical Tool Technology To Modulate Immune Molecular Recognition

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The recognition and elimination of tumors by the immune system is the foundation of modern tumor immunotherapy, the topic of the 2018 Nobel Prize in medicine. The longterm goal of our chemical immunology research program is to design new tools to elucidate the fundamental mechanisms underlying molecular recognition of tumors by antibodies (Ab) and immune cell receptors (ICR). This draws on my extensive experience in the development of synthetic tools called "dimerizers",(D), that modulate the immune recognition of tumors by forming reversible ternary complexes, (Ab:D:L) on the tumor surface through interactions with tumor ligands (L). Dimerizers form ternary complexes by simultaneously binding the protein ligand, L, on the tumor cell surface and an antibody. The bound antibody then activates immune cells through their ICR to destroy the tumor cell through phagocytosis (engulfment) or cytotoxicity (release of cytotoxic granules). Although the factors that control the strength of immune activation against a target cell are not well understood, it is clear that the immune response depends on the number of bound ternary complexes. Forming Ab:D:L ternary complexes with high affinity to occupy all possible ligands on a target cell is a fundamental molecular recognition problem. A major constraint in dimerizer design is that the in vivo concentrations of Ab, and L are so low (nM to pM) that it is difficult to design D to favor the desired ternary complexes over inactive binary complexes Ab:D and D:L. Ternary complex formation is further limited by the fast clearance of D from the circulation in vivo. We aim to design, synthesize and characterize dimerizers that can effectively enhance molecular recognition of target cells by the immune system, by maximizing the stability and formation of ternary vs. binary complexes on the target cell surface in vivo. This will be accomplished through two short term objectives: (1) We will design "covalent dimerizers" (CD) that irreversibly link to antibodies and "kinetically trap" ternary complexes Ab-CD:L (where the dash denotes a covalent linkage). In the event low concentrations of Ab attenuate maximal ternary complex formation on the target surface, we will develop additional bis-reactive CDs that form a covalent linkage to L in addition to Ab to form irreversible ternary complexes Ab-CD-L. (2) We will develop fluorescence polarization kinetic assays to discover and characterize "binding induced" antibody labelling reactions. The new knowledge and technology generated from the proposed research program will provide essential multidisciplinary training while providing technological platforms for new strategies to target foreign pathogens and cells by the immune system.