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In vitro biophysical and pharmacological profiling predicts in vivo efficacy of anti-carfentanil monoclonal antibodies in mice
Hoppe, B. K., Seaman, R. W., Hannon, B., Gay, E., Hicks, D., Baehr, C., Hill, H. J., Pandit, S. G., Baldridge, A., Berner, V., AuCoin, D. P., Runyon, S., & Pravetoni, M. (2025). In vitro biophysical and pharmacological profiling predicts in vivo efficacy of anti-carfentanil monoclonal antibodies in mice. Biochemical and Biophysical Research Communications, 770, 151995. Article 151995. Advance online publication. https://doi.org/10.1016/j.bbrc.2025.151995
Synthetic opioids, including fentanyl and its potent analogs (F/FA) such as carfentanil, are involved in the majority of fatal and non-fatal overdoses in the United States. Despite the availability of the opioid receptor antagonists naloxone and nalmefene to treat overdose, this public health crisis highlights the need for a broader range of treatment options. To support the clinical value of drug-specific monoclonal antibodies (mAbs) as therapeutics for reducing opioid overdose toxicity, the current studies performed in vitro characterization of anti-carfentanil mAbs, and in vivo assessment of their efficacy against carfentanil-induced respiratory depression in mice. To probe the binding interaction between mAbs and carfentanil, this study employed a human mu-opioid receptor (hMOR) calcium mobilization assay and differential scanning fluorimetry. Two of the five mAbs significantly reversed carfentanil-induced respiratory depression in mice. The degree of thermal stabilization of carfentanil-bound mAb correlated with greater efficacy of a given mAb to reverse carfentanil-induced respiratory depression in mice. The reduction of carfentanil-induced hMOR activation stratified mAbs into categories that corresponded, albeit not significantly, to greater in vivo efficacy. These studies indicate that biophysical and pharmacological in vitro analyses can predict the in vivo efficacy of novel mAbs, and support further investigation of mAb-based therapeutics against carfentanil toxicity.
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