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Abstract
To provide a better understanding of the pharmacokinetics-pharmacodynamics relationships of antibody-based drugs, we analyzed several chimeric and humanized monoclonal antibodies or antibody-drug conjugates (ADC) for PK and efficacy among four strains of mice. Notably, antibodies and ADCs displayed a dose-dependent drug disposition profile in the plasma of NSG mice. The increased clearance rate in NSG mice resulted in the reduction of antitumor activity of ADCs. Furthermore, we identified that the abnormal clearance was mediated by Fc-FcγR interaction by comparing antibodies that lack FcγR binding capacity. We also found a high percentage of FcγR-expressing macrophages in the bone marrow, spleen, and liver of NSG mice, which may be responsible for the abnormal distribution of antibodies. Overall, these findings suggest that preclinical evaluation of efficacy and pharmacokinetics of antibodies and ADCs need to consider mouse strain-induced variations.
Highlights
Monoclonal antibodies have become a major class of therapeutics for cancer patients [1, 2]
To evaluate whether the mouse strains of xenograft models have any impact on the pharmacokinetics of antibody or antibody–drug conjugates (ADC), we first measured the plasma concentration of radio-labeled anti-CD30 antibody, aCD30, in four strains of mice: Balb/c, athymic nude, severe combined immunodeficiency (SCID), and NSG. aCD30 is a chimeric IgG1 antibody that recognizes human leukocyte activation marker CD30 [7]
Plasma concentrations at 1 hour, 4 hours, 1 day, 3 days, 7 days, and 10 days after dosing were determined using liquid scintillation counting. These measurements revealed that the plasma clearance profiles of aCD30 were comparable in the Balb/c, nude, and SCID mice (Fig. 1A)
Summary
Monoclonal antibodies have become a major class of therapeutics for cancer patients [1, 2]. These include antibodies that modulate oncogenic signaling pathways, kill tumor cells through effector cell functions, activate antitumor immune responses, engage T cells through bispecific targeting, and deliver cytotoxic payloads in the format of antibody–drug conjugates NSG mice are considered the most immune-compromised, because they lack mature T cells, B cells, and natural killer (NK) cells. They have defective macrophages and dendritic cells due to impaired IL2R signaling. NSG mice offer an excellent host for a variety of cancers, especially those of hematologic origin [6]
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