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. 2010 Feb;28(2):157-9.
doi: 10.1038/nbt.1601. Epub 2010 Jan 17.

Enhanced antibody half-life improves in vivo activity

Jonathan Zalevsky  1 , Aaron K Chamberlain, Holly M Horton, Sher Karki, Irene W L Leung, Thomas J Sproule, Greg A Lazar, Derry C Roopenian, John R Desjarlais
Affiliations

Enhanced antibody half-life improves in vivo activity

Jonathan Zalevsky et al. Nat Biotechnol. 2010 Feb.

Abstract

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. We tested whether antibodies with half-lives extended up to fivefold in human (h)FcRn transgenic mice and threefold in cynomolgus monkeys retain efficacy at longer dosing intervals. We observed that prolonged exposure due to FcRn-mediated enhancement of half-life improved antitumor 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.

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Figures

Figure 1
Figure 1. Increasing antibody affinity to FcRn promotes half-life extension in cynomolgus monkeys
(a) Log-linear serum concentration versus time profiles of anti-VEGF (bevacizumab) antibodies in cynomolgus monkeys. All antibodies were administered via single 60 minute i.v. infusion at 4 mg/kg and serum antibody concentrations were determined using a VEGF antigen-down immunoassay. Results are shown as mean ± standard error (N = 2 for bevacizumab and N = 3 for variants). (b) Log-linear serum concentration versus time profiles of anti-EGFR antibodies in cynomolgus monkeys. Monoclonal antibodies were administered via single 30 minute i.v. infusion at 7.5 mg/kg and serum antibody concentrations were determined using an EGFR antigen-down immunoassay. Results are shown as mean of N = 2 animals per test article.
Figure 2
Figure 2. Improved half-life translates into greater in vivo efficacy
(a) Log-linear serum concentration versus time profiles of anti-VEGF antibodies in hFcRn mice. All antibodies were administered via single i.v. bolus at 2 mg/kg, and serum antibody concentrations were determined using a human immunoglobulin recognition immunoassay. Results are plotted as mean ± standard error (N = 6). (b) Log-linear serum concentration versus time profiles of anti-EGFR antibodies in hFcRn mice. The study design was identical to that described in panel (a) except that serum concentrations were measured with an EGFR antigen-down immunoassay. (c) Xenograft study in hFcRn/Rag1−/− mice comparing activity of native IgG1 and Xtend variant versions of bevacizumab against established SKOV-3 tumors. Tumor volume is plotted versus day post tumor cell injection. Antibodies were dosed 5 mg/kg every 10 days starting on day 35 (indicated by the arrows). N=8 mice/group. * p= 0.028 at 84 days. (d) Xenograft study in hFcRn/Rag1−/− mice comparing activity of anti-EGFR antibodies against established A431 tumors. Tumor volume is plotted versus day post tumor cell injection. Antibodies were dosed 5 mg/kg every 10 days starting on day 10 (indicated by the arrows). N=9 mice/group. * p= 0.005 at 35 days.
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