Th142 - Discovery of a Novel High Affinity Anti-human CD122 Antagonist Monoclonal Antibody (ANA033) That Abrogates IL-2 and IL-15 Signaling for the Treatment of T Cell-mediated Inflammatory and Autoimmune Diseases

Chris Haines – Associate Director, AnaptysBio; Matthew Hsu – Principal Scientist, AnaptysBio; Cheryl Schendel – Sr Research Associate I, AnaptysBio; Pejman Soroosh, PhD – Vice President, AnaptysBio; Stephen Parmley, PhD – Vice President, AnaptysBio; Martin Dahl, PhD – Senior Vice President, AnaptysBio

Abstract Text: T cells play a crucial role in the development and progression of autoimmunity by regulating self-tolerance and participating in inflammation. Signaling through CD122, the beta subunit of the IL-2 and IL-15 receptors, is essential for the function of CD4, CD8 T cells and NK cells. CD122 signaling is also essential for tissue resident memory T cell (Trm) development and survival. Blockade of CD122 leads to elimination and/or reduction of the proliferation of pathogenic T cells in autoimmune diseases. We discovered a high affinity monoclonal antibody, ANA033, that binds CD122 and blocks IL-2 and IL-15 signaling. In vitro, using human peripheral blood, ANA033 inhibited IL-2 and IL-15-mediated primary human CD4, CD8 T cells, and NK cell proliferation. In vivo, we used a xenogeneic graft versus host disease (X-GvHD) model, in which human PBMCs were transferred into immunodeficient mice that constitutively expressed human IL-15. Over-expression of IL-15 in this GvHD model accelerated PBMC engraftment, enhanced weight loss and lethality and promoted the expansion of T cells and NK cells. Importantly, belatacept (CTLA-4 Ig), a reference standard of care that demonstrates survival efficacy in standard GvHD models, failed to maintain survival of the mice. Administration of ANA033 improved survival and suppressed expansion of T cells and NK cells, demonstrated a profound survival benefit superior to belatacept treatment, and continued to maintain survival even after cessation of dosing. Here, we propose that blockade of CD122 may provide great therapeutic value in the treatment of T cell-mediated inflammatory autoimmune disorders.