Background/Purpose: Advanced protein-based therapies targeting B-cells, including glycoengineered CD20 monoclonal antibody obinutuzumab (OBI) and the CD19/CD3 T-cell engager blinatumumab (BLI), show promise for managing severe autoimmune diseases (AIDs). These innovative agents are believed to offer more effective B-cell depletion compared to rituximab (RTX), potentially enabling the elimination of B-cells within affected tissues.

Methods: We performed sequential US-guided inguinal lymph node (LN) biopsies before and after OBI-, BLI-, RTX- and CD19 chimeric antigen receptor T-cell treatment (CAR) in AID patients. Immunohistochemistry (IHC) staining was performed to quantify the number of B cells, plasma cells, follicular dendritic cells (FDCs), follicular T helper cells (TFH), proliferating germinal centre B cells, T cells and macrophages.

Results: Baseline and follow-up LN biopsies from 24 AID patients (7 SLE, 7 SSc, 4 Idiopathic Inflammatory Myositis [IIM], 6 RA) were analysed. Four patients received OBI (3 SLE, 1 IIM), 4 BLI (4 RA), 4 RTX (2 IIM, 2 RA) and 12 CAR (4 SLE, 7 SSc, 1 IIM).Peripheral blood B-cell depletion occurred in all but one BLI-treated patient. IHC quantification of B cells in LNs by CD19 and CD20 staining was performed. In all 12 CAR-treated patients, B cells were completely depleted (p-value for CD19+ and CD20+ cell before vs after CAR = 0.0005). In contrast, in all but one (OBI-treated) patients, B cells were not depleted. OBI showed robust (CD20+: -92%; CD19+: -96%) LN reduction of B-cells. Reduction was less pronounced in BLI-treated patients (CD20+: -69%; CD19+: -47%) and RTX- treated patients (CD20+: -86%; CD19+: -86%). CD138+ plasmablast/plasma depletion was incomplete across all treatments: CAR -59%, OBI -54%, RTX -32% and BLI -7%.Changes in the follicular structure in the LNs were also assessed, including the number of CD23+ FDCs, PD-1+ TFH cells and the proliferation rate in the follicles (Ki67+) before and after treatment. These data were integrated into a combined B-cell compartment architecture score (score range 0 – 9). In all CAR-treated patients the follicular LN architecture was completely disrupted (median B-cell compartment score post-treatment [IQR]: 0.0 [0 – 0]). Among patients treated with protein-based B-cell depleting agents, only one (OBI-treated) exhibited dissolution of the follicular architecture in the LNs, while all others retained some degree of follicular structure. In OBI-treated patients the median [IQR] B-cell compartment score was 4.5 [0.75 – 6.75], in the BLI-treated patients 5.5 [1.75 – 7.75] and RTX- treated patients 4.5 [2.25 – 7.5], all showing maintained follicular structures (Figure 1). Neither T-cell nor macrophages numbers were affected by any of the B-cell targeted treatment agents. Complete depletion was associated with stable drug-free remission, while incomplete depletion required re-treatment with immunomodulatory drugs.

Conclusion: Protein-based B-cell depletion reduces but rarely deplete B cells in LNs leaving the follicular architecture intact and being associated with disease recurrence, whereas CAR ensures consistent full B-cell depletion and follicular structural disruption enabling sustained remission.

Heatmap scoring of follicular dendritic cell (FDC) score, germinal centre proliferation score (GC proliferation score) and the T follicular helper cell score (TFH score) for each treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-depletion-and-lymphoid-follicle-disruption-upon-different-b-cell-depleting-agents/