Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life in vivo. However, this has never been linked with enhanced therapeutic efficacy. Mr Jonathan Zalevsky and Dr John Desjarlais et al. of Xencor at Monrovia, CA, USA, studied if such enhanced antibody half-life improves in vivo activity, as published online in Nature Biotechnology on 17 January 2010.
The article reveals that Xencor’s proprietary Fc engineering extends the half-life of antibodies, while maintaining their potency and extending duration of action. These results demonstrate the potential of Fc engineering to impact the flexibility of route, schedule and dose for nearly any antibody.
“Competition is heating up in biologics, with patent expirations looming and the market demanding drugs that will improve patient compliance”, said Dr Desjarlais, Vice President of research at Xencor and lead author on the study. “Although monoclonal antibodies have reasonably long half-lives, market pressures for less frequent dosing schedules can reduce efficacy. In this Nature Biotechnology paper, our research shows that it is possible with pharmacokinetic engineering to maintain efficacy of antibody drugs, but with less frequent dosing and greater patient convenience”.
To determine whether improved affinity to the neonatal Fc receptor (FcRn) can result in enhanced therapeutic efficacy, Xencor researchers tested whether antibodies with half-lives extended up to five-fold in human FcRn transgenic mice and three-fold in cynomolgus monkeys retain efficacy at longer dosing intervals. Data for the Fc variant constructed in the context of VEGF antibody, bevacizumab (Avastin), which is approved for the treatment of colorectal, lung, breast and renal cancers, showed significantly improved efficacy compared to bevacizumab in tumour xenograft models. “We observed that prolonged exposure due to FcRn-mediated enhancement of half-life improved antitumour activity of Fc-engineered antibodies in an hFcRn/Rag1−/− mouse model. This bridges the demand for dosing convenience with the clinical necessity of maintaining efficacy”.
These results are consistent with the improved efficacy in tumour xenograft models seen with an anti-EGFR antibody variant of cetuximab (Erbitux) versus cetuximab, which is approved for the treatment of colorectal and head and neck cancers.
“While we continue to expand our Fc engineering capabilities and work with partners like Pfizer and Centocor to optimise their antibodies, Xencor is also moving its internal antibody pipeline forward including XmAb2513 in a Phase I trial for lymphoma and pre-clinical antibodies for B-cell malignancies and autoimmune diseases”, added Bassil Dahiyat, President and CEO of Xencor.
References:
Jonathan Zalevsky and John Desjarlais et al. Enhanced antibody half-life improves in vivo activity. Nature Biotechnology. 28:157-9;2010. Published online 2010 January 17.
Data Published in Nature Biotechnology Shows Fc Engineering Improves Antibody Efficacy and Convenience. Xencor Press Release. 2010 January 19.
Source: Xencor Press Release
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