Mechanism-based Changes in Anti-METH Monoclonal Antibody Therapy During Pregnancy

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): (+)-Methamphetamine (METH) is one of the most addictive and heavily abused drugs among pregnant women, yet there are no approved medications for protecting the vulnerable fetus or mother from its adverse health effects. The long-term objective of these studies is to develop antibody-based medications that can be given during pregnancy to protect the mother and fetus from the toxic and addictive effects of METH. While monoclonal antibody (mAb) therapy during human pregnancy is untested, seminal studies from our laboratory in pregnant rats reveal novel and therapeutically important changes to mAb pharmacokinetics (PKs) that compromise antibody efficacy. Specifically, mAb half-life, volume of distribution, and clearance all dramatically change with each gestation stage. Similar gestation-stage specific PK changes have not been reported previously, and the mechanisms that drive these changes are currently unknown. In related studies testing mAb function, certain anti-METH mAb medications (e.g., mAb6H4) show significant in vivo reductions in METH-binding function during the first 24 hrs after administration. This occurred even though >94% of the mAb doses were still present. Importantly, binding affinity for METH (KD) did not correlate with in vivo function despite all mAbs being administered at equal doses and displaying similar PK characteristics. The central hypothesis of this proposal is that the neonatal Fc receptor (FcRn) salvage pathway is both a key regulator of mAb clearance changes during pregnancy and facilitates in vivo reductions in mAb METH- binding function. FcRn is a well-characterized receptor that acts via a pH-dependent salvage mechanism to rescue IgG from catabolic elimination (clearance) and facilitate the passive transfer of IgG from mother to fetus. However, the role of FcRn in regulating mAb PKs during pregnancy is unknown. Furthermore, the low pH environment found in the salvage pathway suggests it could facilitate in vivo modifications to mAbs. To test our hypothesis, we will perform the following aims: 1 - Determine FcRn tissue expression levels during rat pregnancy at times when mAb clearance changes are maximal, 2 - Define the role of the FcRn salvage pathway in regulating IgG clearance during pregnancy, and 3 - Define the role of the FcRn salvage pathway in reducing mAb6H4 METH- binding function. The proposed studies will utilize immunohistochemistry and Western blotting techniques in conjunction with in vivo PK experiments in both pregnant and non-pregnant rats. Instrumental to these studies, anti-METH mAb6H4 will be re-engineered with a single amino acid mutation that eliminates FcRn binding and inhibits passage through the salvage pathway. In addition to providing an excellent training opportunity for a MD/PhD candidate, these innovative studies will contribute to the pre-clinical development of mAb medications for the protection of both the mother and fetus from the dangerous health effects of drugs of abuse. PUBLIC HEALTH RELEVANCE: These studies will define the role of the FcRn salvage pathway in regulating monoclonal antibody (mAb) clearance and function during pregnancy, yielding new insights into the in vivo physiologic processes that affect antibody therapeutic efficacy. This knowledge is expected to advance the preclinical development of safe and effective antibody-based medicines for use in treating pregnant women and their vulnerable fetus(es) from drugs of abuse. Furthermore, due to the ubiquitous role of FcRn in regulating both endogenous and exogenously administered antibodies of the IgG class, these studies will also contribute to our understanding of the regulation of the humoral immune system during pregnant and non-pregnant physiologic states.