Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells.

摘要: Alefacept, an immunomodulatory recombinant fusion protein composed of the first extracellular domain LFA-3 fused to human IgG1 hinge, C(H)2, and C(H)3 domains, has recently been shown in phase II III clinical trials safely reduce disease expression patients with chronic plaque psoriasis. Alefacept modulates function selectively induces apoptosis CD2(+) memory-effector T cells vivo. We have sought gain further understanding mechanisms action that influence biological activity alefacept may contribute its efficacy patient responsiveness. Specifically evaluated is ability activate intracellular signals mediated via CD2 and/or Fc gamma RIII (CD16). Experimentation using isoforms engineered amino acid substitutions C(H)2 impact R binding indicate mediates cognate interactions between expressing CD16 cells, e.g., increase signal-regulated kinase phosphorylation, up-regulate cell surface activation marker CD25, induce release granzyme B. In systems used, this signaling require be through CD16, but not CD2. CD2-transgenic mice confirmed requirement for detection pharmacological effects Thus acts as effector molecule, mediating R(+) (e.g., NK cells) sensitive target cells.