We aim to develop chemical tools using the principles of polyvalent molecular recognition and bio-orthogonal affinity labelling chemistry, to interrogate auto-inhibitory ternary complex equilibrium and modulate cancer cell interactions with immunological machinery. The results of our investigations are intended to contribute new technology to the field of chemical biology, a mechanistic understanding of key immunologically relevant interactions from a molecular level, and support both academic and industrial immune-oncology research efforts

The current program focuses on four specific platforms

Platform 1. Covalent immune recruiting strategy.

Antibody Dependent Cellular Cytotoxicity (ADCC), represents a major mode of action shared by several tumor antibody therapeutics and the host anti-tumor innate immune response. ADCC is minimally dependent on the reversible formation of ternary complexes on the cancer cell surface comprising of antibodies non-covalently associated with both cancer cell and immune effector cell receptors.  Due to the reversibility of this assembly process, ternary complex formation is governed by the affinities and concentrations of several interconverting biological species.  This is highly relevant given the dependence of ADCC potency and efficacy, on the stability and polyvalent display of these ternary complexes on the surface of a target cancer cell.  To probe the dependence of ADCC on ternary complex stability and display, with the goal of using synthetic molecules to control immune protein assembly in its native setting, we are developing covalent chemical labelling strategies to tag and irreversibly dimerize ternary complex proteins.   This is achieved using ligand directed affinity labelling chemistry to site-selectively tag serum antibodies,  cancer receptors, and or effector cell receptors, with relevant small molecule binding ligands of interest.   In this manner, we aim to kinetically control the templating of antibodies and effector cells to the cancer cell surface circumventing the dependence of ADCC on a three body equilibria to exert greater control over the valency of ternary complexes on the cancer cell surface.  These pursuits are anticipated to yield unprecedented mechanistic insight into the anti-tumor innate immune response and mechanism of monoclonal antibody therapeutics while guiding the development of small molecule immunomodulators. 

Platform 2.  Avidity driven synthetic engager therapeutic strategies.

The differential regulation of receptor expression on the surface of cancer cells is known to accompany key steps in disease progression including metastasis and tumor immune evasion. As such, the expression of specific receptors such as her2 or uPAR, are often used as diagnostic markers associated with a particular prognosis.   The over-expression of these antigenic receptors on the surface of cancer cells relative to normal healthy cells presents a unique molecular signature that translates to a selective cancer cell targeting opportunity.  We envision that the resulting polyvalent array of over-expressed surface receptors can be recognized using synthetic probes capable of engaging the surface through non-covalent fined tuned avidity binding interactions.   Towards this goal, sequence defined oligomers and polymers presenting different polyvalent arrays of small molecule cancer receptor binding ligands are being synthesized and evaluated for their ability to chelate cancer cells selectively in the presence of normal healthy cells.  We envision these molecular scaffolds can ultimately be used both as sensors for diagnostic applications and additionally, to recruit biomolecules of interest selectively to the surface of cancer cells. This can be achieved through the incorporation of additional receptor binding capabilities into the scaffold to generate block co-polymers.

Platform 3.  Using molecular recognition to discover and study new ligand directing affinity labelling chemistry.
 

The current arsenal of affinity labelling chemistry is largely confined to alkylation/acylation reactions which in addition to being hydrolytically labile in biological systems, also limits the potential bio-molecular functionality that can be modified to nucleophilic amino acids.  To expand this arsenal with an emphasis on developing new chemistry to site-selectively covalently tag aromatic amino acids and carbohydrate functionality,  we are studying the molecular determinants that govern bio-conjugation effective molarity.  Towards this goal, we are developing molecular recognition systems to control the proximity of aqueous compatible chemical reactants and provide a spectroscopic readout of biomolecule covalent modification that enables for a comprehensive kinetic characterization of the system.

Platform 4. Enhancing immune recognition of low antigen-expressing tumours with multivalent antibody recruiting polymers

Currently, bivalent small molecules require high tumour antigen valency, which poses a problem with tumours that express low antigens. To expand on this, the lab strives to create multivalent polymers that attempt to both amplify and stabilize recruitment to antibodies with these low antigen-expressing tumours, with high avidity. These findings help us demonstrate a therapeutic platform that can help against a wide variety of illness signs linked to varying extracellular protein expression