The Fate and Function of Therapeutic Antiaddiction Monoclonal Antibodies across the Reproductive Cycle of Rats

Abstract

During preclinical development of neuroprotective antiaddiction therapeutic monoclonal antibodies (mAbs) against phencyclidine (PCP) and (ϩ)-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 1/2z ) in nonpregnant females was 6.6 Ϯ 1.6 days, the mAb6B5 t 1/2z significantly changed to 3.7 Ϯ 0.4 days, then 1.4 Ϯ 0.1 days, then 3.0 Ϯ 0.4 days in the second trimester, third trimester, and postpartum periods, respectively (p Ͻ 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).

Chronic anti-phencyclidine monoclonal antibody therapy decreases phencyclidine-induced in utero fetal mortality in pregnant rats

“…1) [30]. The initial mAb dose was a loading dose (D L ) calculated using the equation D L =R*D m , where D m is the maintenance dose and R is the accumulation index.…”

“…MAb6B5 (iv, 45 mg/kg) was administered once per mAb6B5 half-life ( ). MAb6B5 half-life is different in the 2 nd and 3 rd trimester (3 days and 1 day, respectively) [30]. PCP (iv, 1 mg/kg) was administered as indicated (*).…”

“…We also find mAb pharmacokinetics and pharmacodynamics fluctuate in a novel manner during each trimester of rat pregnancy, but an adaptive dosing schedule can maintain mAb-mediated reductions in maternal and fetal brain levels even during chronic PCP-dosing [30]. …”

Treatment with a Monoclonal Antibody against Methamphetamine and Amphetamine Reduces Maternal and Fetal Rat Brain Concentrations in Late Pregnancy

“…To individualize and adapt the therapy for pregnant rats, we calculated mAb dose and time of dosing based on previous findings in rats (Hubbard et al, 2011b). Following mAb4G9 treatment, there was a substantial and statistically significant increase in maternal serum METH and AMP concentrations (Fig.…”

Enzyme-Therapy Approaches for the Treatment of Drug Overdose and Addiction

“…Pharmacokinetic antagonism of a drug could be implemented by using a protein, such as an antibody, which binds tightly to the drug in such a way that the drug–antibody complex cannot cross the BBB [3]. The antibody could be provided with either active immunization (vaccine) [12–14] or passive immunity (monoclonal antibody produced in another host) [15,16]. The blocking action could also be implemented by administration of an appropriately designed enzyme [1,17], or a catalytic antibody (regarded as an artificial enzyme) [18] that not only binds but also accelerates drug metabolism, thereby freeing itself for further binding.…”