Laura M. Rogers, Sarah L. Mott, Brian J. Smith, Brian K. Link, Deniz Sahin, George J. Weiner

Anti-CD20 monoclonal antibody (mAb) therapies, including rituximab and obinutuzumab (GA101) are common treatments for follicular lymphoma (FL). In an effort to better understand the role of complement in mAb action, we recently performed germline SNP profiling on 142 FL patients and found rs3766404 genotype correlated with patient response to rituximab. To assess the role of three SNP-associated complement regulatory proteins (CFH, CFHR1 and CFHR3) in clinical response to anti-CD20 mAb, we studied two cohorts of patients treated with anti-CD20 mAb. Cohorts included the Iowa/Mayo Lymphoma SPORE observational cohort of subjects with a new diagnosis of FL treated with rituximab, and the GAUSS prospective randomized trial cohort of FL subjects randomized to receive single agent rituximab or obinutuzumab. Circulating protein expression was measured for CFH, CFHR1 and CFHR3 and correlated to clinical outcome. rs3766404 genotype correlated with expression of the related downstream genes CFHR1 and CFHR3. Loss of CFHR1 expression correlated with inferior patient outcome in the observational cohort, but not in the GAUSS cohort. Loss of CFHR3 correlated with superior event-free survival in GAUSS subjects treated with obinutuzumab, but not rituximab. We conclude that the relationship between complement regulatory proteins CFHR1 and CFHR3 and response to anti-CD20 mAb therapy varies based on the specific anti-CD20 mAb used. We propose that CFHR3 is a candidate biomarker for obinutuzumab response. Further studies are needed to validate these findings and to better understand how complement pathways and complement regulatory proteins impact on the efficacy of anti-CD20 mAb therapy.