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AB0040 Effects of CC-220, A CRL4 Cereblon E3 Ubiquitin Ligase Modulator, on Immune Responses
  1. Y. Ye,
  2. P. Schafer,
  3. M. Thomas,
  4. D. Weiss,
  5. A. Gaudy,
  6. Z. Yang,
  7. L. Liu,
  8. E. O'Mara,
  9. M. Palmisano
  1. Celgene Corporation, Summit, United States

Abstract

Background Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex, including cullin 4A, DNA damage binding protein 1, and regulator of cullin 1. CC-220 binds to cereblon, affecting the ubiquitin E3 ligase activity and mediating antiproliferative and immunomodulatory effects on lymphocytes. CC-220 is an orally available immunomodulator under development for autoimmune diseases.

Objectives Assess the effects of CC-220 on immune responses to tetanus toxoid (T-cell-dependent antigen) and pneumococcal polysaccharide (T-cell-independent antigen), peripheral T and B lymphocytes, ex vivo cytokine productions, and in vitro rheumatoid factor antibody production from healthy subject samples.

Methods Effects of CC-220 on immune responses were assessed as part of a multiple-ascending dose study in healthy subjects. Protective levels of antitetanus titer were required for enrollment. Six subjects received CC-220 1 mg QD and 3 subjects received placebo QD for 28 days. 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. In addition, the effect of CC-220 on autoantibody production in vitro was assessed using activated and differentiated human peripheral blood mononuclear cells from donors with rheumatoid arthritis.

Results CC-220 reduced immune responses to PPV23, with 60% of 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 with 100% of placebo subjects (2/2) showing 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 CC-220-treated subjects and placebo subjects, with 60% of CC-220 subjects (3/5) and 50% of placebo subjects (1/2) demonstrating a 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%. In ex vivo assays, CC-220 increased IL-2 and interferon-γ production from anti-CD3-stimulated whole blood and inhibited IL-1α and IL-1β production from lipopolysaccharide-stimulated whole blood. In an in vitro assay using cells from donors with rheumatoid arthritis, CC-220 inhibited the production of rheumatoid factor.

Conclusions CC-220 1 mg QD modestly decreased the T-cell-independent antibody response to PPV23, but did not affect the recall response to tetanus toxoid, a T-cell-dependent antibody response. These responses are consistent with CC-220 inhibition of B-cell differentiation while enhancing T-cell cytokine production.

Disclosure of Interest Y. Ye Employee of: Celgene Corporation, P. Schafer Employee of: Celgene Corporation, M. Thomas Employee of: Celgene Corporation, D. Weiss Employee of: Celgene Corporation, A. Gaudy Employee of: Celgene Corporation, Z. Yang Employee of: Celgene Corporation, L. Liu Employee of: Celgene Corporation, E. O'Mara Employee of: Celgene Corporation, M. Palmisano Employee of: Celgene Corporation

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