Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Suppression of Primary SLE B Cells by XmAb5871, An Anti-CD19 Monoclonal Antibody (mAb) That Co-Engages the B Cell Antigen Receptor (BCR) and the FcRIIb Inhibitory Receptor

Chu1,  Seung Y., Ortiz2,  Elizabeth C., Pong1,  Erik, Horton1,  Holly M., Jacob2,  Noam, Stohl2,  William, Szymkowski1,  David E.

Xencor, Inc., Monrovia, CA
Univ Southern California, Los Angeles, CA

Purpose:

XmAb®5871 is a genetically-engineered humanized anti-CD19 mAb that mimics the immunosuppressive effects of immune complexes through its high-affinity binding (0.2 nM) of CD19 (a component of the BCR complex) and simultaneous high-affinity (4 nM) engagement of the B cell inhibitory receptor FcgRIIb (normally a low-affinity receptor for native IgG Fc). Such co-engagement of BCR and FcgRIIb on human B cells potently suppresses activation responses such as intracellular calcium flux, cell proliferation, and class switching. Since FcgRIIb-mediated inhibition may be perturbed in SLE patients, it is critical to determine whether FcgRIIb is a pharmacologically tractable target in SLE. Therefore, we assessed the ability of XmAb5871 to suppress activation of primary SLE and normal B cells.

Method:

SLE patients with elevated circulating levels of at least one SLE-associated autoantibody (anti-dsDNA, anti-Sm, anti-RNP, anti-SS-A, anti-SS-B, anti-cardiolipin) were recruited. B cells were purified from the venous blood of these SLE patients and healthy normal control donors, and cultures containing either XmAb5871 or control mAb were established. In vitro responses of SLE and normal B cells were assessed by suppression of BCR-induced proliferation, intracellular calcium flux, and surface expression of costimulatory molecules. FcgRIIb expression on B cells was measured by flow cytometry and was correlated with the in vitro potency of XmAb5871.

Results:

In vitro studies indicated that the FcgRIIb pathway in SLE B cells can be amplified pharmacologically by XmAb5871. Intracellular calcium signaling was suppressed by XmAb5871 in SLE B cells as well as in normal B cells. Inhibition was critically dependent on amplified FcgRIIb engagement, because control anti-CD19 mAb containing native IgG1 or knocked-out Fc domains were inactive.

Conclusion:

The normal physiological role of immune complexes in suppressing B cell activation can be mimicked by a novel engineered mAb that co-engages FcgRIIb and BCR with high affinity. This inhibitory pathway is functional in SLE B cells, suggesting that a mAb that amplifies FcgRIIb signaling may represent a new therapeutic strategy to suppress autoreactive B cell populations in SLE and related autoimmune diseases.

To cite this abstract, please use the following information:
Chu, Seung Y., Ortiz, Elizabeth C., Pong, Erik, Horton, Holly M., Jacob, Noam, Stohl, William, et al; Suppression of Primary SLE B Cells by XmAb5871, An Anti-CD19 Monoclonal Antibody (mAb) That Co-Engages the B Cell Antigen Receptor (BCR) and the FcRIIb Inhibitory Receptor [abstract]. Arthritis Rheum 2009;60 Suppl 10 :675
DOI: 10.1002/art.25755

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