Investigation of monoclonal antibody CSX-1004 for fentanyl overdose

Paul T. Bremer (), Emily L. Burke, Andrew C. Barrett and Rajeev I. Desai
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Paul T. Bremer: Cessation Therapeutics, Inc.
Emily L. Burke: Harvard Medical School
Andrew C. Barrett: Cessation Therapeutics, Inc.
Rajeev I. Desai: Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-43126-0

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