0990: An Fc-engineered Agonistic anti-pd-1 Antibody Selectively Depletes pd-1⁺ Cells and Attenuates T Cell Activation in vitro and in vivo in a Xenogeneic Graft-versus-host Disease (GvHD) Model

Background/Purpose: PD-1⁺ T cells play a pivotal role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis. Therapeutic antibodies targeting PD-1 with both depleting and agonistic functions have demonstrated the ability to selectively deplete T cells with high PD-1 expression, such as Tph and Tfh cells, and achieved notable clinical responses in patients with rheumatoid arthritis. However, PD-1 is expressed at varying levels across different pathogenic T cell subsets. Cells expressing low to intermediate PD-1 levels, such as cytotoxic CD8⁺ T cell and Th1/Th17 subsets, also play pathogenic roles in autoimmunity. Therefore, therapeutic strategies capable of achieving broad depletion across this full spectrum of PD-1-expressing pathogenic T cells may offer superior benefits in treating autoimmune conditions. ANV200 is a novel, Fc-enhanced PD-1 agonistic antibody, engineered to drive robust and comprehensive depletion of PD-1-expressing pathogenic T cells.

Methods: The effects of ANV200 were assessed in human in vitro reporter cell assays and T cell activity functional assays. Then, the impact of ANV200 on circulating T cell subsets, including PD-1 expression levels, was evaluated in humanized PD-1 mice by flow cytometry. Finally, the efficacy of ANV200 was examined in a xenogeneic graft-versus-host disease (GvHD) model.

Results: ANV200 demonstrated enhanced engagement of FcγRIIIa compared to clinical benchmark antibodies while maintaining the ability to inhibit T cell receptor (TCR) signaling through PD-1 agonism. In addition, ANV200 exhibited a greater capacity to reduce human T cell activation relative to the benchmarks. In vivo, ANV200 selectively depleted PD-1⁺ T cells without inducing a broad lymphopenia, resulting in a shift of the T cell compartment toward a more naïve state in humanized PD-1 mice. In the xenogeneic GvHD model, ANV200 effectively reduced the expansion of donor human T cells.

Conclusion: ANV200 is a novel, highly potent Fc-engineered anti-PD-1 agonistic antibody designed to deplete pathogenic T cells expressing high to low levels of PD-1. By targeting a broad spectrum of antigen-reactive T cells, ANV200 may potentially achieve deeper clinical response in autoimmune diseases.