Immune stimulating agonists such as Toll-like receptor (TLR) agonists can trigger the innate immune system and potentiate anti-tumor immunity.  However, their clinical translation has been limited due to a narrow therapeutic index – off-target immune activation can produce excessive systemic inflammation.  Improving the tolerability and efficacy of such agonists using chemical modifications can broaden their clinical applicability.  One way to improve the therapeutic effect of TLR agonists is to direct delivery by exploiting tumor-specific cues.  It is proposed that metabolic stress in the reductive tumor environment creates an abnormally high number of unpaired cysteines on tumor cell surface proteins.  Here, we exploit that phenomenon using thiol-reactive chemistry to retain polymeric glyco-adjuvants at tumor cell surfaces.  Binding is mediated by pyridyl disulfide (PDS)-containing monomers, which undergo efficient and reversible disulfide exchange.  The adjuvant component is based on our previously reported polymeric TLR7 agonist with pendant mannose groups to target antigen presenting cells.  We now demonstrate that PDS preferentially binds tumor cells <i>in vivo </i>and can be used to retain TLR7 agonists at tumor cell surfaces upon intratumoral injection.  When tethered in the tumor, the polymeric glyco-adjuvant induces a robust anti-tumor response and reduces toxicity associated with both their non-binding counterparts and with clinically-relevant small molecule TLR7 agonists.  Based on these findings, we hypothesize that the modular delivery platform can be expanded to the delivery of other immune-stimulating agonists.

Anchoring of immune-stimulating glyco-adjuvants on the tumor cell surface via disulfide linkage

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