Background/Purpose: Checkpoint antagonist therapeutics have transformed the field of oncology while advancing the understanding of adequate checkpoint activity in preventing autoimmunity. Checkpoint agonism represents a promising and expanding class of therapies for the treatment of autoimmune diseases, including rheumatoid arthritis (RA), where unmet needs persist despite available therapies. The characteristics that confer agonistic properties to an antibody targeting a checkpoint receptor is an evolving science. Binding to membrane proximal regions of suppressive receptors, together with Fc interactions with receptors on opposing cells, can contribute to tight immune synapse formation between the immune cell and antigen presenting cell. This has been proposed to improve potency of agonistic signaling by excluding activating phosphatases from the immune synapse and promoting receptor clustering. Optimization of these characteristics results in improved agonism and depletion carrying the potential for restoration of immune balance and differentiated clinical efficacy. Rosnilimab has been engineered to leverage these important characteristics. It is a PD-1 agonist antibody with an IgG1 backbone designed to optimize inhibitory signaling through the PD-1 receptor and to deplete PD-1-high pathogenic T cells. It is currently in clinical development for RA and other inflammatory conditions.

Methods: Mutations were targeted to surface exposed regions of the PD-1 extracellular domain where antibodies are likely to bind. Surface plasmon resonance of PD-1 structural mutants were used to locate the epitopes of PD-1 agonist molecules. Membrane proximal and distal binding antibodies were studied in in vitro functional assays to assess T cell proliferation and antibody-dependent cellular toxicity (ADCC).

Results: Epitopes of agonistic antibodies were mapped to locations on the PD-1 receptor. The membrane proximal epitope location of rosnilimab was confirmed and binding epitopes for other reference antibodies were identified. Rosnilimab and a membrane distally binding antibody (Reference 1 Antibody) were selected for comparison in functional assays. Rosnilimab demonstrated better inhibition of T cell proliferation and depletion of PD-1+ T cells compared to Reference 1 Antibody, consistent with the hypothesis that membrane proximal binding improves agonistic activity and target cell depletion.

Conclusion: By therapeutically targeting and leveraging natural immune regulatory mechanisms to modulate the pathogenic T cells driving disease, there is an opportunity to dampen the inflammatory cycle and restore immune balance via agonism. Rosnilimab binds to a membrane proximal region of the PD-1 receptor, resulting in optimized inhibition of T cell proliferation, inhibition of cytokine signaling, and PD-1-high T cell depletion. These mechanistic data, robust Phase 1 healthy volunteer safety, PK and translational PD data, and recognized persistent unmet needs in the treatment of RA provide rationale for an ongoing global Phase 2 dose-ranging study of rosnilimab in RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/optimizing-pd-1-agonist-signaling-with-membrane-proximal-binding-of-rosnilimab-a-clinical-stage-pd-1-agonist-igg1-antibody/