An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity That Reverses Carfentanil-Induced Respiratory Depression.
Lisa M EubanksTossapol PholchareeDavid OyenYoshihiro NatoriBin ZhouIan A WilsonKim D JandaPublished in: ACS chemical neuroscience (2023)
The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths in the US over the last 20 years. Though naloxone, a short-acting medication, remains the primary treatment option for temporarily reversing opioid overdose effects, alternative countermeasures are needed. Monoclonal antibodies present a versatile therapeutic opportunity that can be tailored to synthetic opioids and help prevent post-treatment renarcotization. The ultrapotent analog carfentanil is especially concerning due to its unique pharmacological properties. With this in mind, we generated a fully human antibody through a drug-specific B cell sorting strategy with a combination of carfentanil and fentanyl probes. The resulting pan-specific antibody was further optimized through scFv phage display, producing C10-S66K. This monoclonal antibody displays high affinity to carfentanil, fentanyl, and other analogs and reversed carfentanil-induced respiratory depression. Additionally, X-ray crystal structures with carfentanil and fentanyl bound provided structural insight into key drug:antibody interactions.
Keyphrases
- chronic pain
- pain management
- endothelial cells
- high glucose
- monoclonal antibody
- depressive symptoms
- drug induced
- public health
- diabetic rats
- magnetic resonance imaging
- adverse drug
- high resolution
- induced pluripotent stem cells
- healthcare
- pseudomonas aeruginosa
- emergency department
- mass spectrometry
- cystic fibrosis
- anti inflammatory
- oxidative stress
- computed tomography
- physical activity
- stress induced
- structural basis