Open AccessEvaluation of the Ability of Immune Humanized Mice to Demonstrate CD 20‐Specific Cytotoxicity Induced by Ofatumumab
Author(s) -
Semple Kenrick M.,
Gonzaléz Carlos M.,
Zarr Melissa,
Austin José R.,
Patel Vikram,
Howard Kristina E.
Publication year - 2019
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12613
Subject(s) - ofatumumab , cytotoxicity , immune system , monoclonal antibody , immunology , pharmacology , antibody , antibody dependent cell mediated cytotoxicity , biology , cancer research , chemistry , in vitro , biochemistry
CD 20 monoclonal antibodies are well‐established therapeutics for the treatment of B‐cell malignancies. Several mechanisms of target cell killing occur from anti‐ CD 20 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.