Project Details
Description
ABSTRACT. This project will develop monoclonal antibodies (mAb) against toxicity and lethality from accidental
or deliberate exposure to fentanyl, carfentanil, acetylfentanil, and alfentanil. The US has seen dramatic increases
in fatal opioid poisoning due to the widespread availability of fentanyl and fentanyl-like analogs. Because of the
risk for accidental or deliberate mass casualty incidents, the fentanyl chemical family is listed in the DHS
Chemical Threat Risk Assessment list. As a complementary adjuvant strategy to current medications for rescue
of opioid poisoning (e.g., the opioid receptor antagonist naloxone), our team is developing mAb against fentanyl
and its potent analogs to reduce toxicity and lethality in both civilian and defense applications. Our team has
shown that antibody-based strategies effectively reduce opioid distribution to the brain as well as opioid-induced
respiratory depression and bradycardia in mice and rats. Antibodies selectively target the intended opioid, but
do not interfere with endogenous opioids nor with naloxone or other approved medications. Our team has
identified lead first-generation mouse anti-fentanyl mAbs using an antigen-based enrichment strategy to isolate
opioid-specific B cell lymphocytes from immunized mice to generate hybridomas, and mouse/human chimeric
mAb for expression in a suitable mammalian system. The proposed U01 project will further optimize these leads
through an iterative developmental plan. AIM1 focuses on optimization of humanized mAb against fentanyl,
carfentanil, acetylfentanyl, and alfentanil by integrating humanization of lead mouse mAb and immunization of
humanized or transgenic mice. The lead mAb will be used as a benchmark for selection of next-generation
candidates. Leads will be identified for their affinity and selectivity in vitro, and for in vivo efficacy in reducing
antinociception, respiratory depression and lethality in rats. The humanization process will be guided by
biophysical characterization of mAb binding to fentanyl and its analogs by X-ray crystallography. AIM2 focuses
on optimization of lead mAb (Fab or F(ab)2 fragments as alternative options) via polymer-based modifications to
improve half-life and volume of distribution, and increase efficacy against fentanyl and its analogs. AIM3 will test
efficacy of leads co-administered as a multicomponent mAb formulation in combination with opioid antagonists
to provide enhanced protection against respiratory depression and lethality in rats challenged with fentanyl and
its derivatives. To provide proof of scalability, AIM4 tests the efficacy of the lead humanized mAb in a non-human
primate model of opioid-induced respiratory depression. Leads from previous aims will be synthesized at a larger
scale at a contractor site. Finally, AIM5 focuses on drafting a regulatory path toward late-stage development and
commercialization.
Status | Finished |
---|---|
Effective start/end date | 9/1/20 → 7/31/23 |
Funding
- National Institute on Drug Abuse: $813,791.00
- National Institute on Drug Abuse: $775,120.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.