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Biogen, Inc., Cambridge, MA 02142
Alefacept, an immunomodulatory recombinant fusion protein composed
of the first extracellular domain of LFA-3 fused to the human IgG1
hinge, CH2, and CH3 domains, has recently been
shown in phase II and III clinical trials to safely reduce disease
expression in patients with chronic plaque psoriasis. Alefacept
modulates the function of and selectively induces apoptosis of
CD2+ human memory-effector T cells in vivo. We have sought
to gain further understanding of the mechanisms of action that
influence the biological activity of alefacept and may contribute to
its efficacy and patient responsiveness. Specifically evaluated is the
ability of alefacept to activate intracellular signals mediated via CD2
and/or Fc
RIII (CD16). Experimentation using isoforms of alefacept
engineered to have amino acid substitutions in the IgG1 CH2
domain that impact FcR binding indicate that alefacept mediates
cognate interactions between cells expressing human CD2 and CD16 to
activate cells, e.g., increase extracellular signal-regulated kinase
phosphorylation, up-regulate cell surface expression of the activation
marker CD25, and induce release of granzyme B. In the systems used,
this signaling is shown to require binding to CD2 and CD16 and be
mediated through CD16, but not CD2. Experimentation using human
CD2-transgenic mice and isoforms of alefacept confirmed the requirement
for FcR binding for detection of the pharmacological effects of
alefacept in vivo. Thus alefacept acts as an effector molecule,
mediating cognate interactions to activate FcR+ cells
(e.g., NK cells) to induce apoptosis of sensitive CD2+
target cells.
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