Advancing humanized monoclonal antibody for counteracting fentanyl toxicity towards clinical development.

Innovative therapies to complement current treatments are needed to curb the growing incidence of fatal overdoses related to synthetic opioids. Murine and chimeric monoclonal antibodies (mAb) specific for fentanyl and its analogs have demonstrated pre-clinical efficacy in preventing and reversing drug-induced toxicity in rodent models. However, mAb-based therapeutics require extensive engineering as well as in vitro and in vivo characterization to advance to first-in-human clinical trials. Here, novel murine anti-fentanyl mAbs were selected for development based on affinity for fentanyl, and efficacy in counteracting the pharmacological effects of fentanyl in mice. Humanization and evaluation of mutations designed to eliminate predicted post-translational modifications resulted in two humanized mAbs that were effective at preventing fentanyl-induced pharmacological effects in rats. These humanized mAbs showed favorable biophysical properties with respect to aggregation and hydrophobicity by chromatography-based assays, and thermostability by dynamic scanning fluorimetry. These results collectively support that the humanized anti-fentanyl mAbs developed herein warrant further clinical development for treatment of fentanyl toxicity.

Pre-clinical safety and toxicology profile of a candidate vaccine to treat oxycodone use disorder.

Opioid use disorders (OUD) and overdose represent a public health threat, resulting in thousands of deaths annually worldwide. Vaccines offer a promising treatment for OUD and potentially the prevention of fatal overdoses. The Oxy(Gly)4-sKLH Conjugate Vaccine, Adsorbed (Oxy(Gly)4-sKLH) has shown promising pre-clinical efficacy at reducing the behavioral and pharmacological effects of oxycodone. To support its clinical evaluation, a GLP toxicology study was performed to address the safety of Oxy(Gly)4-sKLH. Sprague Dawley rats were vaccinated with either aluminum adjuvant (alum) or vaccine adsorbed on alum. Low and high doses of Oxy(Gly)4-sKLH, equivalent to a 1X or 47X human dose, respectively, were administered every two weeks for a total of four vaccinations. Both vaccine doses induced high antibody titers. Vaccine-related toxicity was assessed postmortem in one experimental group after receiving the fourth immunization of the vaccine's high dose. For the remaining experimental groups, rats were challenged with 1.5 mg/kg/day s.c. oxycodone for 7 days after the fourth vaccination to assess whether concurrent exposure to oxycodone in vaccinated animals resulted in toxicity. All rats, except a subset of the aluminum control and the high dose vaccine groups, were sacrificed following oxycodone exposure. These subsets were allowed a four weeks recovery period prior to euthanasia. In this study, no Oxy(Gly)4-sKLH-related hematology, clinical chemistry, urinalysis, body weight, organ weight, or anatomic pathology toxicological findings were observed. These results demonstrate that the Oxy(Gly)4-sKLH vaccine is well tolerated, is immunogenic even at low doses, and does not produce undesired side effects in rats.

Acceptance of SARS-CoV-2 vaccination and the associated factors among dental health care professionals: A cross-sectional survey.

BACKGROUND: One of the greatest inventions of the 21st century is the development of vaccines against the life-threatening pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whenever a new medication or treatment modality is introduced globally, it is accompanied by anxiety in the general public and among health care professionals. OBJECTIVES: The aim of the study was to explore factors that may influence the acceptance of COVID-19 vaccination among dental health care professionals, as they are the first subgroup in the population to receive the vaccine. MATERIAL AND METHODS: A survey-based cross-sectional study was conducted on 164 health care professionals (general dentists, dental specialists with 2 years of experience after graduation and dental assistants). Data was collected by sending a URL link to the hardand soft-copy questionnaire on Google Forms through all social media platforms. The questionnaire had 2 sections - the 1st part concerned the demographic details and the 2nd part was designed to assess the acceptance of SARS-CoV-2 vaccination among dental health care professionals and the related factors. The normality of the data was assessed with the Shapiro-Wilk test. The Cox regression algorithm was applied to evaluate the factors associated with the acceptance of SARS-CoV-2 vaccination. RESULTS: Out of 164 participants, 85.37% showed a positive attitude toward vaccination and only 7.32% of dental health care professionals were not willing to get vaccinated; out of them, 5 were males and 7 were females. Those who refused to get vaccinated included 3.6% of general dentists, 21.1% of dental specialists and 11.7% of dental assistants. The complications of major concern were fever, myalgia and the lethargic condition immediately after vaccination. CONCLUSIONS: A small percentage of health care professionals declined to get vaccinated against COVID-19 and the main reason was uncertainty about the associated side effects. The respondents were mostly concerned about such side effects as fever, myalgia and the lethargic condition immediately after vaccination.

Contribution of Antibody-Mediated Effector Functions to the Mechanism of Efficacy of Vaccines for Opioid Use Disorders.

Vaccines and mAbs offer promising strategies to treat substance use disorders (SUDs) and prevent overdose. Despite vaccines and mAbs against SUDs demonstrating proof of efficacy, selectivity, and safety in animal models, it is unknown whether the mechanism of action of these immunotherapeutics relies exclusively on the formation of Ab/drug complexes, or also involves Ab-mediated effector functions. Hence, this study tested whether the efficacy of active and passive immunization against drugs of abuse requires phagocytosis, the intact Fc portion of the anti-drug Ab, FcγRs, or the neonatal FcR (FcRn). The efficacy of a lead vaccine against oxycodone was not diminished in mice after depletion of macrophages or granulocytes. Anti-oxycodone F(ab')2 fragments resulted in lower serum levels of F(ab')2 compared with intact mAbs, and F(ab')2s were not as effective as the parent mAbs in reducing distribution of oxycodone to the brain. The efficacy of vaccines and mAbs against oxycodone was preserved in either FcγIII or FcγI-IV ablated mice, suggesting that FcγRs are not required for Ab efficacy. Finally, both active and passive immunization against oxycodone in FcRn-/- mice yielded reduced efficacy compared with wild-type control mice. These data identified a role for FcRn, but not for phagocytosis or Fc-dependent effector functions, in mediating the efficacy of vaccines and mAbs against SUD. This study supports rational design of vaccines and mAbs engineered for maximal neutralization activity and optimal FcRn binding.

Therapeutic and Prophylactic Vaccines to Counteract Fentanyl Use Disorders and Toxicity.

The incidence of fatal overdoses has increased worldwide due to the widespread access to illicit fentanyl and its potent analogues. Vaccines offer a promising strategy to reduce the prevalence of opioid use disorders (OUDs) and to prevent toxicity from accidental and deliberate exposure to fentanyl and its derivatives. This study describes the development and characterization of vaccine formulations consisting of novel fentanyl-based haptens conjugated to carrier proteins. Vaccine efficacy was tested against opioid-induced behavior and toxicity in mice and rats challenged with fentanyl and its analogues. Prophylactic vaccination reduced fentanyl- and sufentanil-induced antinociception, respiratory depression, and bradycardia in mice and rats. Therapeutic vaccination also reduced fentanyl intravenous self-administration in rats. Because of their selectivity, vaccines did not interfere with the pharmacological effects of commonly used anesthetics nor with methadone, naloxone, oxycodone, or heroin. These preclinical data support the translation of vaccines as a viable strategy to counteract fentanyl use disorders and toxicity.

Adjuvant Therapy for Resected Gallbladder Cancer: Analysis of the National Cancer Data Base.

Background: Management of resected gallbladder cancer relies on single-arm trials and retrospective observations. Our objective was to evaluate adjuvant therapy in a nationwide data set using causal inference methods to address sources of bias. Methods: We studied patients with T2-3 or node-positive, nonmetastatic gallbladder cancer, resected with grossly negative margins and reported to the National Cancer Data Base between 2004 and 2011. We defined adjuvant therapy as any chemotherapy within 90 days of surgery, and upfront concurrent chemoradiation as radiation within 14 days of first chemotherapy. After adjusting for missing data and guarantee-time bias, and using propensity score analysis to minimize indication bias, we compared overall survival of patients receiving adjuvant therapies with untreated case subjects. Results: Adjuvant chemotherapy was administered to 28.8% of 4775 patients, and upfront chemoradiation to 13.5%. Treatment was less frequent among patients who were older, patients with comorbidities, and among white Hispanic women. T3 or node-positive disease, microscopically positive margins, or extended resection increased the likelihood of adjuvant therapy. Overall survival at three years was 39.9% (95% confidence interval [CI] = 38.4% to 41.4%) and was unaffected by adjuvant therapy after adjusting for multiple confounders (hazard ratio = 1.01, 95% CI = 0.92 to 1.10). Patients with T3 or node-positive tumors treated with upfront adjuvant chemoradiation had a modest early survival advantage (absolute difference at two years = 6.8%, 95% CI = 1.1% to 12.6%), but survival curves converged after five years of follow-up. Conclusions: The curative potential of current adjuvant therapy in gallbladder cancer is questionable, justifying placebo-controlled investigation of novel chemotherapy combinations or alternative approaches. Chemoradiation may provide a short-term benefit in locally advanced tumors.

Metformin exposure is associated with improved progression-free survival in diabetic patients after resection for early-stage non-small cell lung cancer.

OBJECTIVE: There are little clinical data assessing the antineoplastic effect of metformin in patients with non-small cell lung cancer. We hypothesized that in diabetic patients undergoing pulmonary resection for early-stage non-small cell lung cancer, metformin exposure is associated with improved survival. METHODS: An institutional database was used to identify patients with stage I or II non-small cell lung cancer who underwent pulmonary resection between 2004 and 2013. Patients were divided into 3 cohorts: type II diabetic patients with metformin exposure (cohort A, n = 81), type II diabetic patients without metformin exposure (cohort B, n = 57), and nondiabetic individuals (cohort C, n = 77). Univariate, multivariate, and propensity-matched analyses were performed to assess progression-free and overall survivals between groups. RESULTS: A total of 215 patients with stage I and II non-small cell lung cancer treated with surgical resection were identified for analysis with a median follow-up of 19.5 months. Patients in cohort A had lower T- and N-stage tumors than those in cohorts B or C. However, on multivariate analysis adjusting for age, gender, and T and N stage, progression-free survival was greater for cohort A than cohort B (hazard ratio [HR], 0.410; 95% confidence interval, 0.199-0.874; P = .022) or cohort C (HR, 0.415; 95% confidence interval, 0.201-0.887; P = .017). Likewise, when propensity-matched analyses were performed, cohort A demonstrated a trend toward improved progression-free survival compared with cohort B (P = .057; HR, 0.44; c-statistic = 0.832) and improved progression-free survival compared with cohort C (P = .02; HR, 0.41; c-statistic = 0.843). No differences were observed in overall survival. CONCLUSIONS: Metformin exposure in diabetic patients with early-stage non-small cell lung cancer may be associated with improved progression-free survival, but no effect was seen on overall survival. Further studies are warranted to evaluate if there is a therapeutic role for metformin in the treatment of non-small cell lung cancer.