The fate and function of therapeutic antiaddiction monoclonal antibodies across the reproductive cycle of rats.
During preclinical development of neuroprotective antiaddiction therapeutic monoclonal antibodies (mAbs) against phencyclidine (PCP) and (+)-methamphetamine, we discovered novel, gestation stage-specific changes in mAb disposition spanning the entire reproductive cycle of female rats. Each pharmacological change was independent of mAb dose and antigen target but was precisely coincident with transitions between the gestational trimesters, parturition, and lactation periods of the female reproductive cycle. Whereas anti-PCP mAb6B5 terminal elimination half-life (t(1/2λz)) in nonpregnant females was 6.6 ± 1.6 days, the mAb6B5 t(1/2λz) significantly changed to 3.7 ± 0.4 days, then 1.4 ± 0.1 days, then 3.0 ± 0.4 days in the second trimester, third trimester, and postpartum periods, respectively (p < 0.05 for each change). Initially, these evolving changes in mAb6B5 clearance (3.3-fold), distribution volume (1.8-fold), and elimination half-life (4.7-fold) affected our ability to sustain sufficient mAb6B5 levels to sequester PCP in the bloodstream. However, understanding the mechanisms underlying each transition allowed development of an adaptive mAb-dosing paradigm, which substantially reduced PCP levels in dam brains and fetuses throughout pregnancy. These mAb functional studies also revealed that antidrug mAbs readily cross the placenta before syncytiotrophoblast barrier maturation, demonstrating the dynamic nature of mAb pharmacokinetics in pregnancy and the importance of maintaining maternal mAb levels. These studies provide the first preclinical pregnancy model in any species for chronic mAb dosing and could have important implications for the use of antibody therapies involving blood organ barriers (such as addiction) or other chronic diseases in women of childbearing age (e.g., irritable bowel diseases, multiple sclerosis, breast cancer, rheumatoid arthritis).
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Jonathan J
JJ
Hubbard
Elizabeth M
EM
Laurenzana
D Keith
DK
Williams
W Brooks
WB
Gentry
S Michael
SM
Owens
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005333:Fetus / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D008694:Methamphetamine / Q000276:immunology*; D010622:Phencyclidine / Q000276:immunology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D019966:Substance-Related Disorders / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D008694:Methamphetamine; D010622:Phencyclidine