IL-4 Predicts the Efficacy of a Candidate Antioxycodone Vaccine and Alters Vaccine-Specific Antibody-Secreting Cell Proliferation in Mice

Abstract

Opioid use disorders (OUDs) are a public health concern in the United States and worldwide. Current medications for OUDs may trigger side effects and are often heavily regulated. A novel treatment strategy to be used alone or in combination with existing medications is active immunization with antiopioid vaccines, which stimulate production of opioid-specific Abs that bind to the target drug and prevent its distribution to the brain. Although antiopioid vaccines have shown promising preclinical efficacy, prior clinical evaluations of vaccines targeting stimulants indicate that efficacy is limited to a subset of subjects who achieve optimal Ab responses. We have previously reported that depletion of IL-4 with a mAb increased opioid-specific IgG2a and total IgG, and it increased the number of germinal centers and germinal center T follicular helper cells in response to antiopioid vaccines via type I IL-4 signaling. The current study further investigates the mechanisms associated with IL-4–mediated increases in efficacy and whether IL-4 depletion affects specific processes involved in germinal center formation, including affinity maturation, class switching, and plasma cell differentiation in mice. Additionally, results demonstrate that preimmunization production of IL-4 after ex vivo whole blood stimulation predicted in vivo vaccine-induced Ab titers in outbred mice. Such mechanistic studies are critical for rational design of next-generation vaccine formulations, and they support the use of IL-4 as a predictive biomarker in ongoing OUD vaccine clinical studies.

Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP

“…The concentrations of naloxone (from either free naloxone or cNLX-NP formulations), nalmefene, and fentanyl in the serum and brain from rats in Experiment 3 were measured by LC-MS/MS as described previously ( 35 , 36 ). The limit of detection for naloxone and nalmefene was 1 ng/mL and the limit of quantitation for both was 2.5 ng/mL.…”

ACE2 decoy Fc-fusions and bi-specific killer engager (BiKEs) require Fc engagement forin vivoefficacy against SARS-CoV-2

“…The amino acid (AA) sequences of the neutralizing (CC12.1), and non-neutralizing (CC12.21) SARS-CoV-2 binding variable heavy (VH) and variable light (VL) antibody domains were first described in Rogers et al 58 . To generate SARS-CoV-2 neutralizing antibodies with or without Fc receptor binding (AEFcgR), neutralizing (CC12.1) VH and VL were cloned into previously described pcDNA3.4 expression vectors containing either mIgG2a or mIgG2a-LALA-PG, and mIgK antibody constant domains, respectively 61 . The LALA-PG contains three point mutations in the Fc binding portion that render the Fc portion of the antibody null (AEFcgR): L234A, L235A, P329G 62 .…”