Enhanced antibody half-life improves in vivo activity

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.

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. 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.