Tissue-restricted PD-1 agonists as local immune suppressants - a novel approach to treat cutaneous inflammation and autoimmune diseases

Tissue-restricted immune modulation is a promising approach to overcome issues associated with systemic immunosuppressants. Based on its soluble TCR bi-specific platform Immunocore has engineered targeted PD-1 agonist ImmTAAI® (Immune Modulating Monoclonal TCR Against AutoImmunity) molecules that are designed to modulate the immune system with high specificity at the organ level. ImmTAAI bispecifics consist of a high affinity targeting domain fused to a PD-1 agonist moiety to inhibit autoreactive T cells. As reported recently (Curnock et al., 2021), ImmTAAI molecules bound to target cell peptide HLA activate the PD-1 pathway on interacting T cells and potently inhibit inflammation and cytotoxic activity. Importantly, these targeted PD-1 agonists are inactive when free in solution and are only able to inhibit T cells when tethered to target cells. These features make them an attractive and novel platform to treat T cell driven autoimmune and inflammatory diseases. Having obtained initial proof of concept data, this targeted approach is progressing through preclinical development with skin-directed PD-1 agonists to potentially treat T cell driven dermatological indications, including Vitiligo and Atopic Dermatitis (AD). For this, two separate skin-restricted targets have been identified and characterized: a novel peptide-HLA melanocyte antigen, and a highly abundant HLA-unrestricted target found on skin antigen presenting cells. We present mechanistic data to show that these skin-directed PD-1 agonist ImmTAAI when tethered to target cells, potently inhibit T cell activation and inflammatory cytokine release. Overall, the PD-1 agonist ImmTAAI described here have the potential to deliver potent immune modulation, with high organ and cellular specificity. We hypothesize that these targeted PD-1 agonist ImmTAAI could help restore immune tolerance in the skin and provide significant clinical benefit to patients with vitiligo and AD without the risk of systemic immunosuppression.