Xencor’s Xtend™ Fc domains increase binding affinity to the receptor FcRn. FcRn is present inside lysosomes in endothelial cells lining the blood vessels and functions to rescue antibodies from the degradation that makes most proteins short-lived in circulation.
As a result of interactions with FcRn, all antibodies have half-lives ranging from a few days to a few weeks, allowing less frequent dosing for antibody drugs than most other biologics.
We have engineered a series of Fc variants that increase binding of the Fc domain to FcRn to further increase circulating half-life. Our lead Xtend Fc domain has two amino acid substitutions and has shown up to three-fold increases of in vivo half-life for a number of different antibodies in preclinical models and in human clinical trials. Our Xtend technology is currently in eight clinical-stage programs and one approved therapy, Alexion’s Ultomiris® (ravulizumab-cwvz).
Half-life extension can be exploited to potentially improve therapeutic antibody performance in several ways:
- Increased dosing interval, providing superior patient convenience and likely compliance. Reduced dosing frequency results in lower drug use in aggregate, reducing cost of goods.
- Lower drug quantities at the same dosing interval as the parent antibody. This can simplify dosage formulation and enable subcutaneous formulation. Cost of goods is reduced, as well.
- Higher drug levels using the same dose and dosing interval as the parent antibody, resulting in longer drug exposure and potentially better efficacy.