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Background and Objectives: Rituximab is an anti-CD20 monoclonal antibody approved in the first-line treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab pharmacokinetics shows a time dependency possibly related to changes in the target antigen amount over time. The purpose of this study was to quantify the influence of both CD20 antigenic mass and the FcγRIIIA genetic polymorphism on rituximab pharmacokinetics in CLL., Methods: Rituximab pharmacokinetics was described in 118 CLL patients using a semi-mechanistic model including a latent target antigen turnover, which allowed the estimation of rituximab target-mediated elimination in addition to the endogenous clearance., Results: Target-mediated elimination rate constant increased with the baseline CD20 count on circulating B cells (p = 0.00046) and in patients with the FCGR3A-158VV genotype (p = 0.0016). Physiologic elimination of antigen was lower in the Binet C disease stage (p = 0.00018). The effects of these covariates on rituximab concentrations were mainly visible at the beginning of treatment. Body surface area also increased central and peripheral volumes of distribution (p = 1.3 × 10 -5 and 0.0015, respectively)., Conclusions: A pharmacokinetic model including target-mediated elimination accurately described rituximab concentrations in CLL and showed that rituximab 'consumption' (target-mediated elimination) increases with increasing baseline antigen count on circulating B cells and in FCGR3A-158VV patients., Clinical Trial Registration: NCT01370772.

Purpose of Review: Obinutuzumab is a new anti-CD20 monoclonal antibody which demonstrated clinical superiority compared with rituximab in a recent phase III study. There is a need to better understand how this antibody differs from rituximab and why it could modify the landscape of the treatment of CD20 malignancies in the near future., Recent Findings: Antibody-dependent cellular cytotoxicity plays a critical role in clinical activity of rituximab. To increase antibody-dependent cellular cytotoxicity, a strategy improving the affinity between the Fc portion of the antibody and FcγRIIIa expressed by effector cells has been recently developed. This strategy modifies the carbohydrate located between the two Fc arms. Thus, the lack of fucose on IgG oligosaccharide improves binding to FcγRIII and antibody-dependent cellular cytotoxicity. Obinutuzumab recognized a CD20 epitope different from that bound by rituximab. This property confers different features to obinutuzumab mechanisms of action with a noncaspase-dependent direct-cell death and the lack of complement-dependent cytotoxicity. Obinutuzumab demonstrated significant activity in animal models, and phase I or II studies showed clinical activity in different subtypes of CD20 diseases., Summary: Obinutuzumab, a type II glycoengineered monoclonal antibody, is characterized by an increased antibody-dependent cellular cytotoxicity and direct-cell death but no complement-dependent cytotoxicity. Recent clinical data demonstrated a superiority of obinutuzumab compared with rituximab, suggesting that this antibody should be, in the future, the backbone of the treatment of B-lymphoproliferative disorders.