Second generation CD2-targeting LFA-3 fusion protein SBT115301 to restore immune homeostasis in autoimmune disease

In autoimmunity, an imbalance of effector (T_eff) and regulatory (T_reg)T cells contributes to inflammation and tissue destruction. CD2, highly expressed on T_eff and at lower levels on T_reg and naive T cells (T_n), is an attractive target for depleting T_eff at sites of inflammation. SBT115301 is a second generation CD2-targeting fusion protein containing the cognate receptor of CD2, lymphocyte function associated antigen-3 (LFA-3; CD58). In <i>in vitro</i> and <i>in vivo</i> studies, SBT115301 preferentially decreased CD2^hi-expressing T_eff cells compared to T_reg and T_n. In a phase 1 clinical trial, SBT115301 selectively reduced memory T cells. SBT115301 was well tolerated aside from decreases of CD4⁺ T cells in some participants in the highest dose IM and IV cohorts. Anti-drug antibodies decreased exposure of SBT115301 in some participants without affecting the pharmacodynamics. These data support further study of SBT115301 as a monotherapy or in combination with other drugs in autoimmune indications.