Preclinical Development of an anti-5T4 Antibody-Drug Conjugate: Pharmacokinetics in Mice, Rats, and NHP and Tumor/Tissue Distribution in Mice.
2015
The pharmacokinetics of an antibody (huA1)–drug (auristatin microtubule disrupting MMAF) conjugate, targeting 5T4-expressing cells, were characterized during the discovery and development phases in female nu/nu mice and cynomolgus monkeys after a single dose and in S-D rats and cynomolgus monkeys from multidose toxicity studies.
Plasma/serumsamples were analyzed using an ELISA-based method for antibody and conjugate (ADC) as well as for the released
payloadusing an LC-MS/MS method. In addition, the distribution of the Ab, ADC, and released
payload(cys-mcMMAF) was determined in a number of tissues (tumor, lung, liver, kidney, and heart) in two tumor mouse models (H1975 and MDA-MB-361-DYT2 models) using similar LBA and LC-MS/MS methods. Tissue distribution studies revealed preferential tumor distribution of cys-mcMMAF and its relative specificity to the 5T4 target containing tissue (tumor). Single dose studies suggests lower CL values at the higher doses in mice, although a linear relationship was seen i...
Keywords:
-
Correction
-
Source
-
Cite
-
Save
29
References
16
Citations
NaN
KQI