Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

Abstract

Introduction Recently, increasing FcRn binding by Fc engineering has become a promising approach for prolonging the half-life of therapeutic monoclonal antibodies (mAbs). This study is the first to investigate the optimization of an allometric scaling approach for engineered mAbs based on cynomolgus monkey data to predict human pharmacokinetics. Methods Linear two-compartmental model parameters (clearance [CL]; volume of distribution in the central compartment [ V c ]; inter-compartmental clearance [ Q ]; volume of distribution in the peripheral compartment [ V p ]) after the intravenous (IV) injection of engineered mAbs (M252Y/S254T/T256E or M428L/N434S mutations) in cynomolgus monkeys and humans were collected from published data. We explored the optimal exponent for allometric scaling to predict parameters in humans based on cynomolgus monkey data. Moreover, the plasma concentration–time profile of engineered mAbs after IV injection in humans was predicted using parameters estimated based on an optimized exponent. Results For engineered mAbs, a significant positive correlation between cynomolgus monkeys and humans was observed for CL, but not for other parameters. Whereas conventional exponents (CL: 0.8, Q : 0.75, V c : 1.0, V p : 0.95) previously established for normal mAbs showed poor prediction accuracy for CL and Q of engineered mAbs, the newly optimized exponents (CL: 0.55, Q : 0.6, V c : 0.95, V p : 0.95) achieved superior predictability for engineered mAbs. Moreover, the optimized exponents accurately predicted plasma mAb concentration–time profiles after IV injection of engineered mAbs in humans. Conclusions We found that engineered mAbs require specially optimized exponents to accurately predict pharmacokinetic parameters and plasma concentration–time profiles after IV injections in humans based on cynomolgus monkey data. This optimized approach can contribute to a more accurate prediction of human pharmacokinetics in the development of engineered mAbs.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PF‐06817024 in Healthy Participants, Participants with Chronic Rhinosinusitis with Nasal Polyps, and Participants with Atopic Dermatitis: A Phase 1, Randomized, Double‐Blind, Placebo‐Controlled Study

“…However, the t 1/2 observed in this first‐in‐human clinical study was substantially longer (ranging from approximately 83 to 94 days after administration of a single iv dose in healthy participants), indicating a greater‐than‐expected t 1/2 extension that was not initially predicted based on the nonclinical data. The underlying biological mechanism for such a discrepancy is still unknown; however, this observation is in alignment with a report that demonstrates that optimized nonconventional allometric scaling exponents may be required to accurately predict PK parameters of monoclonal antibodies that have been engineered for t 1/2 extension 17 . Additionally, a physiologically based PK modeling framework has been proposed as a valuable tool to improve predictions for such antibodies 18 .…”

“…The underlying biological mechanism for such a discrepancy is still unknown; however, this observation is in alignment with a report that demonstrates that optimized nonconventional allometric scaling exponents may be required to accurately predict PK parameters of monoclonal antibodies that have been engineered for t 1/2 extension. 17 Additionally, a physiologically based PK modeling framework has been proposed as a valuable tool to improve predictions for such antibodies. 18 The long half-life of PF-06817024 observed in healthy participants and both patient populations is substantially longer compared to that of a typical monoclonal antibody (11-30 days), 22 reflecting the successful bioengineering of PF-06817024 toward that goal with the aim to potentially provide prolonged therapeutic efficacy and/or a more efficient dosing regimen.…”

“…PF-06817024 was specifically engineered to have an extended t 1/2 , using M428L/N434S mutations, while retaining full IL-33 neutralization activity. 17,18 Based on this, along with the potential for broad inhibition of type 2 inflammation, it can be hypothesized that PF-06817024 may provide superior and more durable efficacy compared with other biologics that are currently available for the treatment of atopic diseases or other anti-IL-33 antibodies under development. Since IL-33 does not play an essential role in clearing bacterial and viral infections, PF-06817024 would be expected to have a favorable safety profile.…”

A bispecific antibody NXT007 exerts a hemostatic activity in hemophilia A monkeys enough to keep a non-hemophiliac state

“…We designed NXT007 to improve pharmacokinetics and reduce clearance by incorporating a set of mutations into the C H 3 region to increase binding to the neonatal Fc receptor (FcRn) at acidic pH. 24 Indeed, the clearance (CL) of NXT007 was 2.46 mL/day/kg after intravenous (IV) administration at 2 mg/kg, and CL/F in the range of 2.68–3.37 mL/day/kg after a single subcutaneous (SC) administration at 0.02, 0.2, and 2 mg/kg, which is lower than that of typical monoclonal antibodies including emicizumab, 12,18,25 and the SC bioavailability was in the range of 82.0–92.2% (Figure 5B). The plasma elimination half-life of NXT007 was 22.1 days after IV administration at 2 mg/kg, and in the range of 19.6–24.4 days after a single SC administration at 0.02, 0.2, and 2 mg/kg (Figure 5B).…”

Independent Analysis of the Results of the First Infant Immunization Campaign with Beyfortus® (Nirsevimab, Monoclonal Antibody against RSV, Bronchiolitis Virus): Mixed Results, Identification of Biases and Possible Role and Mechanisms of ADE (Antibody Dependent Enhancement)

“…No direct measurements have been made in infants injected with nirsevimab [74]. However, when studying pharmacokinetics in cynomolgus monkeys after IV injection, the elimination phase can be poorly assessed, especially at low plasma concentrations [75]. When the results are used to estimate the levels achieved in humans by IM, this extrapolation could lead to clinical inefficiency.…”