Treatment of Adverse Effects of Excessive Phencyclidine Exposure in Rats with a Minimal Dose of Monoclonal Antibody

Laurenzana, Elizabeth M.; Gunnell, Melinda G.; Gentry, W. Brooks; Owens, S. Michael

doi:10.1124/jpet.103.053140

Cited by 26 publications

(42 citation statements)

References 18 publications

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“…Although fetal PCP data from GD9 confirm that mAb-bound drug can increase total drug levels, whereas the placental barrier is mAb-permeable (Fig. 4), both of these possible concerns are addressed by remembering that mAb-associated increases in total drug levels consist almost entirely of inactive, mAb-bound drug (Laurenzana et al, 2003b). Thus, the apparently extended drug t 1/2z in mAb-dosed animals does not reflect an extended t 1/2z of the active drug, but instead of the inactive, mAb-bound drug.…”

Section: Changing Mab Pharmacokinetics Across Rat Reproductive Cycle 419mentioning

confidence: 99%

“…mAb drug binding does not affect mAb disposition (i.e., mAb fate) (Laurenzana et al, 2003a). In addition, mAb-induced changes in the disposition of the target drug of abuse can directly reflect mAb function in mother and fetus (Rivière et al, 2000;Laurenzana et al, 2003b). Another advantage is that anti-PCP and anti-METH mAbs do not seem to cross blood-organ barriers such as the brain and testis to any great extent, but they do effectively remove PCP and METH from these organs (Proksch et al, 2000;Laurenzana et al, 2003a).…”

Section: Introductionmentioning

confidence: 99%

“…Another advantage is that anti-PCP and anti-METH mAbs do not seem to cross blood-organ barriers such as the brain and testis to any great extent, but they do effectively remove PCP and METH from these organs (Proksch et al, 2000;Laurenzana et al, 2003a). This redistribution of target drug out of brain tissue is the mechanism of action for the neuroprotection mediated by these antiaddiction mAb medications (Laurenzana et al, 2003b;Keyler et al, 2006;Pentel et al, 2006). These findings suggest the potential for similar effects at the maternal blood-brain barrier, fetal blood-brain barrier, and blood-placental barrier, as suggested by studies in nearterm, nicotine-treated pregnant rats (Keyler et al, 2005a,b).…”

Section: Introductionmentioning

confidence: 99%

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

Hubbard¹,

Laurenzana²,

Williams³

et al. 2010

J Pharmacol Exp Ther

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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).

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Section: Changing Mab Pharmacokinetics Across Rat Reproductive Cycle 419mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hubbard¹,

Laurenzana²,

Williams³

et al. 2010

J Pharmacol Exp Ther

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“…Immunization has been studied as a potential treatment strategy for a variety of drug addictions, including heroin (Killian et al, 1978), cocaine (Carrera et al, 2001;Kantak et al, 2001), phencyclidine (Laurenzana et al, 2003), methamphetamine (McMillan et al, 2004), and nicotine Cerny et al, 2002;Lindblom et al, 2002;Sanderson et al, 2003;Carrera et al, 2004). Vaccines consisting of the drug linked to a foreign carrier protein elicit the production of drug-specific antibodies that bind drug in serum and extracellular fluid, reduce the unbound drug concentration, and reduce drug distribution to brain.…”

mentioning

confidence: 99%

Monoclonal Nicotine-Specific Antibodies Reduce Nicotine Distribution to Brain in Rats: Dose- And Affinity-Response Relationships

Keyler¹,

Roiko²,

Benlhabib³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Vaccination against nicotine is being studied as a potential treatment for nicotine dependence. Some of the limitations of vaccination, such as variability in antibody titer and affinity, might be overcome by instead using passive immunization with nicotinespecific monoclonal antibodies. The effects of antibodies on nicotine distribution to brain were studied using nicotine-specific monoclonal antibodies (NICmAbs) with K d values ranging from 60 to 250 nM and a high-affinity polyclonal rabbit antiserum (K d ‫؍‬ 1.6 nM). Pretreatment with NICmAbs substantially increased the binding of nicotine in serum after a single nicotine dose, reduced the unbound nicotine concentration in serum, and reduced the distribution of nicotine to brain. Efficacy was directly related to antibody affinity for nicotine. Efficacy of the highest affinity NICmAb, NICmAb311, was dose-related, with the highest dose reducing nicotine distribution to brain by 78%. NICmAb311 decreased nicotine clearance by 90% and prolonged the terminal half-life of nicotine by 120%. At equivalent doses, NICmAb311 was less effective than the higher affinity rabbit antiserum but comparable efficacy could be achieved by increasing the NICmAb311 dose. These data suggest that passive immunization with nicotinespecific monoclonal antibodies substantially alters nicotine pharmacokinetics in a manner similar to that previously reported for vaccination against nicotine. Antibody efficacy is a function of both dose and affinity for nicotine.

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“…The mAbs reduced METH effects even at doses that were 1/3rd mol-eq to the amount of METH in the rat at the time of mAb dosing. Similarly, we have previously shown that an anti-PCP mAb effectively reduces brain PCP concentrations and locomotor effects even when the body burden of PCP is many times greater than the number of mAb binding sites, 17,18 and 20,21 The projected effective human antibody doses for our mAbs will be smaller and in line with those for approved mAbs. This is in part because of the differences in cerebral blood flow in man compared with rats leading to a larger amount of mAb reaching the human brain, resulting in a more effective reduction in METH CNS effects.…”

Section: Feasibility Of Dosesmentioning

confidence: 75%

Pharmacological effects of two anti-methamphetamine monoclonal antibodies

Laurenzana¹,

Stevens²,

Frank³

et al. 2014

Human Vaccines & Immunotherapeutics

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This lead candidate selection study compared two anti-(C)-methamphetamine (METH) monoclonal antibodies (mAb) to determine their ability to reduce METH-induced locomotor effects and redistribute METH and (C)-amphetamine (AMP) in a preclinical overdose model. Both mAbs have high affinity for METH, but mAb4G9 has moderate and mAb7F9 has low affinity for AMP. In the placebo-controlled behavioral experiment, the effects of each mAb on the locomotor response to a single 1 mg/kg intravenous (IV) METH dose were determined in rats. The doses of mAb binding sites were administered such that they equaled 1, 0.56, 0.32, and 0.1 times the molar equivalent (mol-eq) of METH in the body 30 min after the METH dose. METH disposition was determined in separate animals that similarly received either a 1 or 0.32 mol-eq dose of mAb binding sites 30 min after a 1 mg/kg METH dose. Total METH-induced distance traveled was significantly reduced in rats that received the highest three doses of each mAb compared with saline. The duration of METH effects was also significantly reduced by mAb7F9 at the highest dose. The disposition of METH was altered dose-dependently by both mAbs as shown in reductions of volume of distribution and total clearance, and increases in elimination half-life. These data indicate that both mAbs are effective at reducing METHinduced behavior and favorably altering METH disposition. Both were therefore suitable for further preclinical testing as potential human medications for treating METH use; however, due to results reported here and in later studies, mAb7F9 was selected for clinical development.

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Treatment of Adverse Effects of Excessive Phencyclidine Exposure in Rats with a Minimal Dose of Monoclonal Antibody

Cited by 26 publications

References 18 publications

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

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

Monoclonal Nicotine-Specific Antibodies Reduce Nicotine Distribution to Brain in Rats: Dose- And Affinity-Response Relationships

Pharmacological effects of two anti-methamphetamine monoclonal antibodies

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