Anti-C1QA monoclonal antibody, clone 0B8

Purpose: Complement may play a role in the clinical response to rituximab and other monoclonal antibody-based therapies of cancer. The purpose of this study was to explore the relationship between the C1qA([276]) polymorphism and the clinical response to rituximab in patients with follicular lymphoma. Experimental Design: Genotyping for C1qA([276A/G]) was done in 133 subjects with follicular lymphoma treated with single-agent rituximab, and correlation with clinical response was done using Cox regression analysis. Results: Prolonged remission was observed among subjects that responded clinically to rituximab therapy and were carriers of the A allele compared with homozygous G subjects. Homozygous G subjects had a time to progression of 282 days, whereas A-allele carriers had a time to progression of 708 days [hazard ratio, (HR), 2.5; 95% confidence interval (95% CI), 2.0-3.1; P = 0.02]. Among subjects who achieved complete remission, homozygous G subjects had a time to progression of 250 days, whereas A-allele carriers had a time to progression of 1,118 days (HR, 4.5; 95% CI, 4.1-4.8, P = 0.04). The difference persisted after controlling for CD32 and CD16 polymorphisms. In patients who responded to rituximab used as first-line agent, a linear trend was observed among the C1qA([276]) genotypes, with homozygous A subjects achieving complete response at a higher rate compared with heterozygous or homozygous G subjects. Conclusions: Our findings indicate that polymorphisms in the C1qA gene may affect the clinical response and duration of response to rituximab therapy of follicular lymphoma. These results could have direct implications on designing antibodies with improved efficiency and enhance our understanding of the role of complement in monoclonal antibody therapy.

P>Recent studies have tested genetic variation at the C1QA, C1QB and C1QC (complement component 1, q subcomponent, A chain, complement component 1, q subcomponent, B chain and complement component 1, q subcomponent, c chain) loci in relation to systemic lupus erythematosus (SLE) risk. Evidence for a significant effect of C1Q locus gene polymorphisms on SLE predisposition remains unclear. We aimed to identify associations between common C1Q polymorphisms and SLE risk and serum C1q, C3 and C4 levels. We performed family-based association tests in 295 nuclear families with one affected proband. Tag-single nucleotide polymorphisms (SNPs) ranging from 35 center dot 4 kb upstream of the C1QA gene to 28 kb downstream of the C1QB gene were selected to represent the entire C1Q gene locus. We performed transmission disequilibrium tests for affectation status and continuous traits, including C1q, C3 and C4 levels using family-based association tests (FBAT). There was no evidence for a significant role of C1Q locus gene polymorphisms in SLE risk predisposition. The strongest association was observed with a variant in the 3'UTR region of the C1QB gene (rs294223, P = 0 center dot 06). We found nominally significant associations with a second variant (rs7549888) in the 3'UTR region of the C1QB gene and C1q (P = 0 center dot 01), C3 (P = 0 center dot 004) and C4 levels (P = 0 center dot 01). In a large family-based association study of C1Q gene cluster polymorphisms no evidence for a genetic role of C1Q locus SNP in SLE risk predisposition was obtained in patients of European ancestry. This is in contrast to other cohorts, in which single variants associated with C1Q, C3 and C4 levels and nephritis have been studied and shown associations.