Background/Purpose: Production of pathogenic autoantibodies by inappropriately self-reactive plasma cells (PC) is a hallmark of autoimmune diseases. MEDI-551 is an anti-CD19 antibody which is expected to significantly deplete PC, distinct from anti-CD20 targeted therapy which does not deplete PC. Low PC numbers in whole blood (usually 0.5% of total cells) and their instability, make it challenging to implement routine flow cytometry assays to measure PC levels in clinical trials. To address this limitation, we developed a robust gene-expression based assay which can be easily implemented in clinical trials to measure the PC population. 

Methods: Based on literature and whole genome microarray analysis of sorted cellular fractions and purified PC, we identified genes (IGHA, IGJ, IGKC, IGKV, and BCMA) whose expression is highly significantly enriched in PC. We developed a signature score combining expression levels of these genes to estimate PC counts in whole blood. Flow-sorted cells obtained from healthy volunteers were used to assess the sensitivity, specificity, and reliability of detecting alterations in PC numbers using this gene expression signature. 

Results: We demonstrated clinical utility of this PC signature using samples from patients enrolled in CP-200, a Phase I single dose-ranging trial (N = 27) of MEDI-551 in scleroderma. MEDI-551 caused a robust depletion of the PC gene signature in whole blood and skin, with maximum depletion reaching approximately 98% and 90%, respectively. Up to 90% B cell depletion was observed in blood and skin. At 85 days following MEDI-551 administration, the last timepoint evaluated, PC and B cell levels recovered up to 65% of baseline. 

Conclusion: This newly developed gene-expression based PC signature provides a robust and straightforward way to accurately measure PC levels in the clinic. By applying this PC signature, we demonstrated significant depletion of PC cells by MEDI-551, an anti-CD19 monoclonal antibody. In combination with flow cytometry data, this PC signature will help inform dosing decisions for future trials of MEDI-551, as well as provide the ability to correlate clinical activity with baseline PC levels or with the extent/duration of PC depletion.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-gene-expression-signature-to-monitor-depletion-of-plasma-cells-following-medi-551-anti-cd19-administration/