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Abstract Number: 2873

Epratuzumab Induces Broad Inhibition of B Cell Receptor Proximal Signaling but Has Opposing Effects on Distal Signaling in B Cell Subsets: A Profile of Effects on Functional Immune Signaling By Single Cell Network Profiling

Alison Maloney1, Drew Hotson2, Stephen Rapecki1, Gianluca Fossati1, Simon Lumb1, David Rosen2, Santosh Putta2, Nikil Wale2, David Spellmeyer2, Alessandra Cesano2, Rachael Hawtin2 and Anthony Shock1, 1UCB Pharma, Slough, United Kingdom, 2Nodality Inc., South San Francisco, CA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: B cells, Biologic agents, Biologics, Cell Signaling and systemic lupus erythematosus (SLE)

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Session Information

Title: B cell Biology and Targets in Autoimmune Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose

Epratuzumab is a humanized monoclonal antibody targeting the B cell-specific protein CD22 and is in Phase 3 clinical trials in patients with systemic lupus erythematosus (SLE). Epratuzumab does not deplete B cells, rather, the mechanism of action centers on CD22 regulatory activity of B cell receptor (BCR) modulation, via inhibition of specific BCR-driven phosphorylation events (Syk, PLCγ2) and Ca2+ flux.1 The aim of this study was to assess the effects of epratuzumab on receptor activation and BCR signaling across multiple B cell subsets in peripheral blood mononuclear cells (PBMC) from a large cohort of healthy donors.

Methods

Single Cell Network Profiling (SCNP) is a multiparametric, flow cytometry-based technology that enables simultaneous analysis of signaling networks in multiple immune cell subsets.2 BCR modulated signaling (anti-IgG/anti-IgM) was profiled by SCNP in PBMC from 60 healthy donors (HD) across naïve (CD27-/IgD+), switched memory (CD27+/IgD-) and unswitched memory (CD27+/IgD+) B cell subsets. Surface receptor (CD22, CD19), proximal (Syk, Slp76, BTK, PLCγ2) and distal (Akt, Erk, S6, p38, IkBa, NFκB-p105) signaling was interrogated 5 or 15 minutes post modulation in the presence and absence of epratuzumab (10mg/ml), which had been pre-incubated with cells for 1 hour.  

Results

On-target epratuzumab activity in B cells was identified as induction of pCD22 Tyr807, most pronounced in naïve B cells (p<0.001). Broad inhibition of all examined BCR-proximal signaling (p<0.0001) was observed in the whole B cell population with the most pronounced effects observed in the switched memory population. Strong inhibition of BCR modulated pCD19 (p<0.001) was also seen in this population, which may contribute to inhibition of BCR activation events. Inhibition of distal signals was demonstrated specifically in the switched memory B cell population whilst conversely, in the naïve B cell subset, evidence for activation of distal signaling (p<0.0001) was observed. Interestingly, weak activation of pAkt was observed in both naïve and switched memory B cells.

Conclusion

Broad analysis of functional immune signaling across B cell subsets identified epratuzumab inhibition of BCR-proximal signaling, supporting an inhibitory role in BCR activation. Opposing effects on distal signaling were identified in the naïve and memory populations. In switched memory B cells inhibition of pCD19 and downstream signals was demonstrated. In contrast, in naïve B cells activation of distal signals was observed. These data have implications for understanding the functional consequences of epratuzumab treatment on B cell pathologic activity in patients with autoimmune diseases such as SLE.

References

1. Sieger N. Arthritis Rheum 2013;65:770

2. Cesano A. Cytometry Part B 2012;82B:158


Disclosure:

A. Maloney,

UCB Pharma,

3;

D. Hotson,

Nodality Inc.,

3;

S. Rapecki,

UCB Pharma,

3;

G. Fossati,

UCB Pharma,

3;

S. Lumb,

UCB Pharma,

3;

D. Rosen,

Nodality Inc.,

3;

S. Putta,

Nodality Inc.,

3;

N. Wale,

Nodality Inc,

3;

D. Spellmeyer,

Nodality Inc.,

3,

Nodality Inc.,

1;

A. Cesano,

Nodality Inc.,

3;

R. Hawtin,

Nodality Inc.,

3;

A. Shock,

UCB Pharma,

3.

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