FC066: Circulating Anti-Rituximab Antibodies Do Not Affect Response to Rituximab in Steroid-Dependent Nephrotic Syndrome
Authors: Angeletti Andrea , Bruschi Maurizio , Lugani Francesca , Caridi Gianluca , Eugenio Verrina Enrico , Colucci Manuela , Cravedi Paolo , Vivarelli Marina , Marco Ghiggeri Gian 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Previous studies reported that the chimeric anti-CD20 monoclonal rituximab may lead to the production of anti-rituximab antibodies (Anti-RTX-Abs), due to the chimeric nature, impairing the efficacy of further infusions. In the context of glomerulonephritis, recent findings have described that the incidence of anti-RTX-Abs development may affect the efficacy of rituximab in paediatric steroid dependent nephrotic syndrome (SDNS) [Fujinaga et al. Pediatr Nephrol. 2020 Oct; 35(10): 2003–2008] and in membranous nephropathy [Boyer-Suavet et al. Front Immunol. 2020 Jan 13; 10: 3069]. The improved patient outcomes and cost-effectiveness have led to the development of a new generation of fully human anti-B cell agents in haematological and autoimmune diseases [Klomjit et al. Am J Kidney Dis. 2020 Dec; 76(6): 883–888]. Therefore, elucidating the role of Anti-RTX-Abs with the aim to develop personalized therapies is mandatory. In a randomized clinical trial, we compared the efficacy of fully humanized anti-CD20 antibody ofatumumab versus rituximab in children and young adults with SDNS [Ravani et al. JASN Oct 2021, 32 (10) 2652–2663].

METHOD
We randomized 140 subjects to single infusion of rituximab or ofatumumab. Follow-up was of 24 months. We measured anti-rituximab IgG antibodies (LISA- TRACKER, Theradiag© Croissy Beaubourg, France) at the enrollment in 64/140 (46%) patients who previously received rituximab, regardless of the randomization arm, and at 6 months in 54/70 of the patients in the rituximab arm. (Fig. 1) Median time of last rituximab treatment was 36 months (13–54) before enrollment.

RESULTS
Anti-RTX-Abs were detected in none of the patients receiving more than or equal to one rituximab infusion before enrollment. At 6 months, Anti-RTX-Abs are detected in 14/54 patients (26%) who received rituximab (Fig. 2A). Patients developing anti-RTX-Abs or not had similar characteristics at enrollment. At T6, anti-RTX-Abs was not statistically different comparing who received rituximab before enrollment and who did not (Fig. 2B).
Of the 54 patients treated with rituximab, 35 (65%) relapsed in 12 months of follow-up. Incidence of patients with anti-RTX-Abs at T6 was not statistically different comparing who experienced relapse with who did not (Fig. 2C). Time to relapse is reported in Fig. 2D. According to the protocol study, the 35 relapsing received a further infusion of rituximab. In this subgroup, incidence of patients with anti-RTX-Abs at T6 was not statistically different comparing who experienced further relapses with who did not (Fig. 2E).
Both patients with and without anti-RTX-Abs had similar levels of total B-cell counts before rituximab therapy and at month 6 and 12 thereafter, showing similar B-cell reconstitution (Fig. 2F). We found similar percentages for memory B-cells comparing patients with and without Anti-RTX-Abs at enrollment, at month 6 and at month 12 of follow-up (Fig. 2G).

CONCLUSION
We evaluated the impact of Anti-RTX-Abs in a prospective study considering a large cohort of SDNS patients who received additional rituximab in case of relapse after a single infusion (375 mg/m2). According to the literature, we reported the development of Anti-RTX-Abs after a single infusion, which seems to persist for limited time. However, in contrast to previous findings, the development of Anti-RTX-Abs does not represent an unfavourable factor, which may limit the efficacy and the safety of further infusions. The prospective design of our study, in contrast to previous ones, represents one of the major strength of the present work. Moreover, Anti-RTX-Abs did not affect total and memory B-cell reconstitution following rituximab treatment.