CD2 x IL2RG bispecific antibodies synergistically modulate lymphocyte activation, resulting in suppression of inflammation and prevention of GVHD 2258985

Abstract Introduction The common γ chain (γc, IL2RG) is a shared receptor subunit for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 that regulates lymphocyte survival and activation. Mutations in IL2RG cause X-linked severe combined immunodeficiency (XSCID), underscoring its essential role in immune homeostasis. Dysregulated lymphocyte activation drives autoimmune and inflammatory diseases, yet current therapies such as corticosteroids and JAK inhibitors have limited efficacy in many patients and are often poorly tolerated. We developed CD2 x IL2RG bispecific antibodies that block IL2RG-mediated γc cytokine signaling and CD2-dependent co-stimulation, providing a dual-mechanism approach that combines direct inhibition of both pathways with CD2-targeted selectivity for IL2RG blockade on CD2+ lymphocytes (T and NK cells). Methods Bispecific CD2 x IL2RG antibodies were engineered with blocking arms for IL2RG and CD2 to inhibit γc cytokine and co-stimulatory pathways selectively on T and NK cells. These molecules were evaluated for inhibition of γc signaling, suppression of T-cell cytotoxicity and cytokine release in vitro, and mitigation of GVHD in vivo. Results By combining γc- and CD2-blocking arms, CD2 x IL2RG antibodies exhibited up to a three-log increase in potency for inhibiting γc-mediated signaling compared with monovalent or bivalent anti-IL2RG antibodies. The bispecifics synergistically suppressed T-cell—mediated lysis and reduced IFN-γ, and IL-2 production. In a human PBMC-engrafted NSG GVHD model, treatment initiated one week after PBMC transfer and continued weekly or biweekly for five weeks prevented mortality and weight loss, maintaining durable survival until study end. Conclusion Dual targeting of IL2RG and CD2 enables selective, avid blockade of cytokine and co-stimulatory signaling, leading to potent suppression of effector activity and GVHD. This approach may provide durable immune control while minimizing systemic immunosuppression from broad γc pathway inhibition. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)