Cell-targeted PD-1 agonists that mimic PD-L1 are potent T cell inhibitors

Abstract

The PD-1/PD-L1 pathway is a key immune checkpoint that regulates T cell activation. There is strong rationale to develop PD-1 agonists as therapeutics against autoimmunity, but progress in this area has been limited. Here, we generated TCR targeting, PD-1 agonist bispecifics called ImmTAAI molecules that mimic the ability of PD-L1 to facilitate the co-localization of PD-1 with the T cell receptor (TCR) complex at the target cell-T cell interface. PD-1 agonist ImmTAAI molecules specifically bound to target cells and were highly effective in activating the PD-1 receptor on interacting T cells to achieve immune suppression. Potent PD-1 antibody ImmTAAI molecules closely mimicked the mechanism of action of endogenously expressed PD-L1 in their localization to the target cell-T cell interface, inhibition of proximal TCR signalling events and suppression of T cell function. At picomolar concentrations, these bispecifics suppressed cytokine production and inhibited CD8 T cell-mediated cytotoxicity in vitro. Crucially, in soluble form the PD-1 ImmTAAI molecules were inactive and hence could avoid systemic immunosuppression. This study outlines a promising new route to generate more effective, potent, tissue-targeted PD-1 agonists that can inhibit T cell function locally with the potential to treat autoimmune and chronic inflammatory diseases of high unmet need.

Anti–PD-1 antibodies recognizing the membrane-proximal region are PD-1 agonists that can down-regulate inflammatory diseases

“…We did not observe any agonist clone working without cross-linking to Fc receptors. Other forms of PD-1 stimulators, such as recombinant TCR conjugated with PD-L1 or anti–PD-1 antibody fragment, were also designed to work at the interface between T cells and APCs ( 11 ). When T cells meet with APCs, the spatial segregation of membrane proteins has been reported ( 31 , 32 ).…”

“…Because CD80 binding to PD-L1 inhibits its interaction with PD-1, the blockade of CD80-PD-L1 binding promoted PD-1-dependent immunoregulation by increasing PD-L1 availability (10). A bispecific T cell engager-like approach was also undertaken in the major histocompatibility (MHC)-oriented delivery of PD-L1 to inhibit PD-1-expressing T cells (11). Compared with PD-L1, which interacts with PD-1 with moderate affinity (12)(13)(14)(15), high-affinity binding of antibodies to PD-1 has potential advantages as a pharmacological PD-1-stimulatory agent.…”

Mechanism‐driven strategies for prevention of rheumatoid arthritis

“…Newer approaches under development include the use of PD-1 agonists to induce a generalized state of unresponsiveness. 101 In addition to targeting T cells and their products, restriction of antigen presentation or recognition of citrullinated targets by inhibitors of PADs may limit the ability of ACPA autoantibodies, as well as T cell responses, to recognize their target antigens, among other potential effects that may influence later stages of the disease. 102 Beyond antigen-agnostic interventions, antigen-specific tolerance is an important potential approach.…”

Novel PET Imaging of Inflammatory Targets and Cells for the Diagnosis and Monitoring of Giant Cell Arteritis and Polymyalgia Rheumatica

“…Since the development of both GCA and PMR as consequences of PD-1/PD-L1 inhibition therapy of cancer patients has been reported ( 79 , 80 ), the use of these radiotracers for the imaging of GCA and PMR may potentially worsen the disease and is therefore not feasible. However, with the rise of PD-1 agonists ( 81 – 84 ), future applications of these PD-1 agonist-based radiotracers may prove to be useful as a theranostic approach in these diseases.…”