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Abstract Number: 0859

Biomarkers of B-cell Depletion and Response in a Randomized, Controlled Trial of Obinutuzumab for Proliferative Lupus Nephritis

Ed Vital1, Philippe Remy2, Luis Fernando Quintana Porras3, Laurent Chiche4, Dominique Chauveau5, Richard Furie6, Thomas Schindler7, Jay Garg8, Matthew Cascino8, Zahir Amoura9, Andrea Doria10, Cary Looney8 and Dario Roccatello11, 1University of Leeds; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, 2APHP Groupe Hospitalier Henri-Mondor, Creteil, France, 3Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain, 4Hôpital Européen, Marseille, France, 5Hôpital Rangueil, Centre Hospitalier Univ de Toulouse, Toulouse, France, 6Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, 7F. Hoffmann-La Roche Ltd., Basel, Switzerland, 8Genentech, Inc., South San Francisco, CA, 9Hôpital Pitié-Salpêtrière, Paris, 10University of Padua, Padua, Italy, 11S Giovanni Hospital, Univ of Turin, Turin, Italy

Meeting: ACR Convergence 2020

Keywords: autoimmune diseases, B-Lymphocyte, Biomarkers, immunology, Lupus nephritis

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Session Information

Date: Saturday, November 7, 2020

Session Title: SLE – Treatment Poster I

Session Type: Poster Session B

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

Background/Purpose: Incomplete B-cell and plasmablast depletion, as measured using highly sensitive flow cytometry (HSFC), is associated with lower response rates following rituximab in SLE [1]. Enhanced B-cell depletion with the type II anti-CD20 monoclonal antibody obinutuzumab resulted in increased renal responses in proliferative lupus nephritis (LN) in the NOBILITY trial (NCT02550652) and will be further evaluated in the Phase 3 REGENCY trial (NCT04221477). The objective of this analysis was to measure peripheral B-cells, B-cell subsets (naïve, memory and plasmablast) and B-cell activating factor (BAFF) levels and to assess associations between B-cell depletion and renal response in LN patients in a clinical trial of obinutuzumab.

Methods: 126 patients with active Class III/IV LN were randomized to obinutuzumab or placebo infusions in combination with mycophenolate and glucocorticoids. Peripheral B-cells were measured using a HSFC method with a lower limit of quantitation of 0.441 cells/μL. Serum levels of BAFF were evaluated using ELISA. Sustained depletion was defined by total B-cells below the limit of detection at both weeks 24 and 52. Renal response definitions from Phase 2 NOBILITY and Phase 3 REGENCY trials were used.

Results: Obinutuzumab resulted in rapid depletion of total B-cells, memory and naïve B-cells, and plasmablasts from peripheral blood, with 88% of obinutuzumab patients depleted to < 0.441 total B-cells/μL at week 2 (Figure). Mean serum BAFF increased from 4,585 pg/mL at baseline to 14,601 pg/mL at week 52 in the obinutuzumab group. Sustained B-cell depletion was achieved in 32/52 (62%) of patients with complete data and was associated with a higher renal response rate at week 76 (Table), although patients who achieved sustained depletion also had lower baseline proteinuria and serum creatinine.

Conclusion: Obinutuzumab, a type II anti-CD20 mAb, mediated rapid, complete and sustained depletion of peripheral B-cells and plasmablasts and large increases in serum BAFF. Similar to previous reports, sustained B-cell depletion was associated with increased renal response though there may have been confounding factors. REGENCY is being conducted to further evaluate the therapeutic hypothesis with obinutuzumab in LN.

References:

  1. Md Yusof MY et al. Ann Rheum Dis. 2017;76:1829-36.

Figure. Mean levels of selected biomarkers over time by treatment group.

Table. Data from NOBILITY at week 76 by depletion status at weeks 24 and 52.


Disclosure: E. Vital, Roche/Genentech, 2, 5; P. Remy, None; L. Quintana Porras, None; L. Chiche, None; D. Chauveau, None; R. Furie, AstraZeneca/MedImmune, 2, 5; T. Schindler, Roche, 1, 3; J. Garg, Genentech, 1, 3; M. Cascino, Genentech, 1, 3; Z. Amoura, Roche, 2; A. Doria, GlaxoSmithKline, 5, 8, Eli Lilly, 5, 8, Roche, 5, 8, Janssen, 5, 8, Pfizer, 5, 8; C. Looney, Genentech, 1, 3; D. Roccatello, None.

To cite this abstract in AMA style:

Vital E, Remy P, Quintana Porras L, Chiche L, Chauveau D, Furie R, Schindler T, Garg J, Cascino M, Amoura Z, Doria A, Looney C, Roccatello D. Biomarkers of B-cell Depletion and Response in a Randomized, Controlled Trial of Obinutuzumab for Proliferative Lupus Nephritis [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/biomarkers-of-b-cell-depletion-and-response-in-a-randomized-controlled-trial-of-obinutuzumab-for-proliferative-lupus-nephritis/. Accessed April 16, 2021.
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