Investigation of monoclonal antibody CSX-1004 for fentanyl overdose

• Published in: Nature communications Vol. 14; no. 1; p. 7700
• Main Authors: Bremer, Paul T., Burke, Emily L., Barrett, Andrew C., Desai, Rajeev I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.12.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/436; 631/250/251; 631/378/1689/5; 64/60; 64/86; 82/1; Analgesics, Opioid - pharmacokinetics; Animal models; Animals; Antibodies, Monoclonal; Cross-reactivity; Drug overdose; Drug Overdose - drug therapy; Fatalities; Fentanyl; Human tissues; Humanities and Social Sciences; Humans; Mice; Monoclonal antibodies; multidisciplinary; Narcotics; Operant conditioning; Opioids; Overdose; Oxycodone; Pain perception; Pharmacokinetics; Rats; Respiratory Insufficiency - chemically induced; Respiratory Insufficiency - drug therapy; Science; Science (multidisciplinary); United States; United States; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43126-0

The opioid crisis in the United States is primarily driven by the highly potent synthetic opioid fentanyl leading to >70,000 overdose deaths annually; thus, new therapies for fentanyl overdose are urgently needed. Here, we present the first clinic-ready, fully human monoclonal antibody CSX-1004 with picomolar affinity for fentanyl and related analogs. In mice CSX-1004 reverses fentanyl antinociception and the intractable respiratory depression caused by the ultrapotent opioid carfentanil. Moreover, toxicokinetic evaluation in a repeat-dose rat study and human tissue cross-reactivity study reveals a favorable pharmacokinetic profile of CSX-1004 with no safety-related issues. Using a highly translational non-human primate (NHP) model of respiratory depression, we demonstrate CSX-1004-mediated protection from repeated fentanyl challenges for 3-4 weeks. Furthermore, treatment with CSX-1004 produces up to a 15-fold potency reduction of fentanyl in NHP respiration, antinociception and operant responding assays without affecting non-fentanyl opioids like oxycodone. Taken together, our data establish the feasibility of CSX-1004 as a promising candidate medication for preventing and reversing fentanyl-induced overdose. Fentanyl continues to drive the opioid crisis by contributing to >70,000 deaths per year in the US. Here, the authors investigate a candidate medication for fentanyl overdose prevention (monoclonal antibody CSX-1004) demonstrating its mitigation of fentanyl’s effects in preclinical animal models.