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 for synthetic
opioids and that can 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. This antibody, C10-S66K, 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.