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CD20 monoclonal antibodies are well‐established therapeutics for the treatment of B‐cell malignancies. Several mechanisms of target cell killing occur from anti‐CD20 therapy, including complement‐dependent cytotoxicity (CDC) cell lysis and antibody‐dependent cell‐mediated cytotoxicity. Human Fc receptors (FcRs) are required to mediate these functions and are either not present or not cross‐reactive in mice and most animal species. In contrast, some nonhuman primates have cross‐reactive FcR; however, their cellular expression and function may differ from humans. Therefore, we tested bone marrow‐liver‐thymus (BLT) humanized mice to determine if they could recapitulate the pharmacokinetics (PKs), pharmacodynamics, and potential toxicities of ofatumumab, for which CDC is the predominant mechanism of action. Ofatumumab‐treated BLT mice depleted B cells in a dose‐dependent manner in all tissues sampled and recapitulated the PKs observed in humans, suggesting that BLT mice can mediate the CDC effector mechanism associated with biological drug products. [ABSTRACT FROM AUTHOR]