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Abstract Number: 1081

The CRL4CRBN E3 Ubiquitin Ligase Modulator CC-220 Inhibits BAFF-Mediated Plasmablast Differentiation and Immunoglobulin Secretion from Class Switched CD27+IgD- Memory and Lupus-Associated CD27-IgD- Double Negative B-Cells

Yumi Nakayama1, Jolanta Kosek1, Lori Capone2, Peter H. Schafer3 and Garth Ringheim1, 1Inflammation and Immunology Translational Development, Celgene Corporation, Summit, NJ, 2Celgene Corporation, Summit, NJ, 3Department of Translational Development, Celgene Corporation, Summit, NJ

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: B cell memory, B cells, BAFF, Plasmablasts and antibodies

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Session Information

Date: Monday, November 14, 2016

Session Title: B Cell Biology and Targets in Autoimmune Disease - Poster I: SLE and Sjögren's

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:  Changes in the ratio of circulating memory, naive, and double negative CD27–IgD– B cell subsets are associated with a higher disease activity index in systemic lupus erythematosus (SLE) patients. Little is known about the soluble factors that may induce plasmablast differentiation from B-cell subtypes infiltrating inflamed tissue environments where they have proximity to, but often spatially separated from T-cells. We investigated the potential for SLE-associated soluble BAFF, IL-2 and IL-21 to drive plasmablast differentiation from B-cell subsets in a T-cell contact independent manner and whether CC-220, a Cullin Ring Ligase 4 Cereblon (CRL4CRBN) E3 Ubiquitin Ligase Modulator, has an impact on generating potential autoantibody producing cells. The objective of the study was to determine the potential of BAFF, IL-2 and IL-21 to induce plasmablast differentiation from memory, naive, and lupus-associated double negative B-cell subsets and to determine the impact of CC-220 on differentiation and proliferation within these B-cell populations.

Methods:  We investigated the effects of CC-220 on plasmablast differentiation from purified B-cell subsets in in vitro models mimicking germinal center T cell contact dependent (CD40L, IL-2, IL-21) and extra-germinal center T-cell contact independent (BAFF, IL-2, IL-21) systems. Plasmablast differentiation and antibody secretion was measured 5 days post treatment of CD27+ memory B-cells and CD27– naive B-cells. Sorted B-cell subsets based on the CD27 memory and the IgD class switch markers were also tested: CD27–IgD+ naïve; CD27+IgD– switched memory (SMe); CD27+IgD+ non switched memory (NSM); and CD27–IgD– double negative (DN) B cells. Plasmablast differentiation and antibody production in the absence or presence of CC-220 were analyzed by flow cytometry and ELISA, respectively.

Results:  BAFF, IL-2, and IL-21 in combination induced proliferation and plasmablast differentiation in SMe and DN B-cells, but not NSM or naive B-cells. Induced IgG secretion by BAFF, IL-2, and IL-21 was observed only from SMe and DN B-cells. Induced IgM secretion by BAFF, IL-2, and IL-21 was observed from SMe, to a lesser degree DN, but not from NSM or naive B-cells. CD40L, IL-2, and IL-21 induced B-cell proliferation and differentiation from all four subpopulations, with SMe producing the largest amount of IgG secretion followed by DN and DP and little from naive B-cells. Similar to IgG, IgM secretion was induced most from SMe, followed by NSM and DN in the CD40L, IL-2, IL-21 system. CC-220 inhibited plasmablast differentiation and antibody production in all cases, with different efficacy depending on the B-cell subpopulations and stimuli.

Conclusion:  In the presence of IL-2 and IL-21, BAFF induced proliferative and plasmablast differentiation effects are only observed on class switched CD27+IgD– memory and DN CD27–IgD– B-cells. This is in contrast to CD40L, IL-2, and IL-21,which drives B-cell proliferation and differentiation in all four subpopulations tested. In all conditions used to induce B-cell proliferation and plasmablast differentiation, CC-220 inhibited these processes at clinically relevant concentrations (1-10 nM).


Disclosure: Y. Nakayama, Celgene, 3; J. Kosek, Celgene, 1,Celgene, 3; L. Capone, Celgene, 1,Celgene, 3; P. H. Schafer, Celgene, 1,Celgene, 3; G. Ringheim, Celgene, 3,Celgene, 1.

To cite this abstract in AMA style:

Nakayama Y, Kosek J, Capone L, Schafer PH, Ringheim G. The CRL4CRBN E3 Ubiquitin Ligase Modulator CC-220 Inhibits BAFF-Mediated Plasmablast Differentiation and Immunoglobulin Secretion from Class Switched CD27+IgD- Memory and Lupus-Associated CD27-IgD- Double Negative B-Cells [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/the-crl4crbn-e3-ubiquitin-ligase-modulator-cc-220-inhibits-baff-mediated-plasmablast-differentiation-and-immunoglobulin-secretion-from-class-switched-cd27igd-memory-and-lupus-associated-cd27-igd-do/. Accessed March 7, 2021.
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