The pH-dependent binding of Igs to the neonatal FcR (FcRn) plays a critical role in the in vivo homeostasis of IgGs. Modulating the interaction between Fc and FcRn through protein engineering is one method for improving the pharmacokinetics of therapeutic Abs. Recent studies disputed the direct relationship between increasing FcRn affinity and improved pharmacokinetic properties. In this work, we studied the pharmacokinetics of two human IgG1 Fc variants in cynomolgus monkey to further clarify the affinity-pharmacokinetic relationship. First, we report a number of novel Fc point mutations and combination variants, including some with primate-specific FcRn-binding improvements. By studying these variants along with some previously described variants across a wide range of affinities, we discovered a direct correlation of pH 6 affinity improvements with neutral pH improvements, suggesting that all of the tested variants exhibit similar pH dependency in FcRn binding. We then evaluated the pharmacokinetics of variants N434A and N434W, which, respectively, gave ∼4- and 80-fold improvements in pH 6-binding affinity to both human and nonhuman primate FcRn. Surprisingly, clearance of N434W was similar to that of wild type. N434W is the first variant studied in primates that exhibits significant binding to FcRn at pH 7.4, and its clearance substantiates the principle that too much affinity improvement, i.e., beyond that of N434W, does not yield improved pharmacokinetics. In contrast, N434A exhibited a ∼2-fold decrease in clearance in cynomolgus monkey, supporting the notion that modest increases in pH 6 FcRn affinity can result in improved pharmacokinetics in primates.
The moderate level of P-gp mediated transport and low affinity of SV, SVA, and AVA for P-gp inhibition compared to systemic drug levels suggest that drug interactions due to competition for P-gp transport is unlikely to be a significant factor in adverse drug interactions. Moreover, the inconsistencies between P-gp inhibition studies and P-gp transport of SV, SVA, and AVA indicate that the inhibition studies are not a valid means to identify statins as Pgp substrates.
Purpose. Anti-ETBR-MC-vc-PAB-MMAE (anti-ETBR-vc-E) is an antibody-drug conjugate (ADC) targeting the Endothelin B receptor. It comprises the humanized IgG1 anti-ETBR monoclonal antibody and a potent anti-mitotic agent, monomethyl auristatin E (MMAE), linked through MC-VC-PAB linker. Anti-ETBR antibody and its conjugate cross-react with mouse, rat, cynomolgus monkey and human, which provides an opportunity to compare and evaluate the impact of normal tissue expression on ADC disposition in preclinical species. Methods. Anti-ETBR-vc-E was administered intravenously in mice (0.5 and 5 mg/kg), rats (0.5 and 5 mg/kg), and cynomolgus monkeys (0.3 and 1 mg/kg). The samples were assayed for total antibody and conjugated antibody concentrations in mice and rats while total antibody and antibody-conjugated MMAE concentrations were determined in monkeys. Concentration-time data were used to estimate the pharmacokinetic parameters. Results. The pharmacokinetic behavior of the ADC was characterized by monitoring and comparing total antibody, conjugated antibody, and antibody-conjugated MMAE disposition. The clearances for all three analytes were dose-independent after intravenous administration in mice, rats, or cynomolgus monkeys over the dose range studied. Conjugated antibody and antibody-conjugated MMAE clearances were approximately 2-fold higher than total antibody clearance. Clearance of total antibody in rat was approximately 2-fold higher than in mouse and monkey, with values of 19.4, 7.91, and 8.99 mL/day/kg, respectively. Half-life ranged from 8 to 10 days and volume of distribution ranged from 37 to 40 mL/kg. Conclusions. The pharmacokinetics of anti-ETBR-vc-E total antibody was dose proportional in rodents and monkey suggesting that the presence of cross-reactive antigen in the preclinical species had no impact on clearance. All three species showed a relatively higher deconjugation clearance compared to total antibody clearance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B192.
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