Y. Ye, P. Schafer, M. Thomas, D. Weiss, A. Gaudy, Z. Yang, L. Liu, E. O'Mara, M. Palmisano; Celgene, Summit, NJ
BACKGROUND: CC-220 is an orally available immunomodulator under development for autoimmune diseases. Effects of CC-220 on immune responses to tetanus toxoid (T cell-dependent antigen) and pneumococcal polysaccharide (T cell-independent antigen) were assessed.
METHODS: Protective levels of antitenanus titer were required for enrollment. Six healthy subjects received 1 mg CC-220 once daily for 28-days, and 3 subjects received placebo. On Day 14, subjects received vaccines of 23-valent pneumococcal polysaccharide (PPV23) and tetanus toxoid. Antibody responses, peripheral B- and T-cell counts, and ex vivo cytokines were measured.
RESULTS: CC-220 reduced immune responses to PPV23, with 60% CC-220-treated subjects (3/5) showing normal response (≥ 2-fold of baseline or > 1 μg/mL increase from baseline in antibodies against > 70% serotypes), compared to 100% placebo subjects (2/2) having normal responses. However, the reduction was mild as all CC-220 subjects were able to mount normal immune responses to 12 out of 23 serotypes. Immune responses to tetanus toxoid were similar between placebo and CC-220-treated subjects, with 60% CC-220 subjects (3/5) and 50% placebo subjects (1/2) demonstrating 4-fold increase from baseline in antitetanus IgG titer. Following 14-days of CC-220 dosing, peripheral B cell counts were decreased from baseline by 79%, and T cell counts were decreased by 22%; however, CC-220 increased T cell cytokine production from anti-CD3-stimulated whole blood ex vivo.
CONCLUSION: CC-220 at 1 mg QD modestly decreased the T-independent antibody response to PPV23, but did not affect the recall response to tetanus toxoid, a T-dependent antibody response. These responses are consistent with CC-220 inhibition of B-cell differentiation while enhancing T-cell stimulation.