Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys

Datta‐Mannan, Amita; Witcher, Derrick R.; Lu, Jirong; Wroblewski, Victor J.

doi:10.4161/mabs.4.2.19364

Cited by 40 publications

(42 citation statements)

References 21 publications

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“…Moreover, the rates of association and dissociation of IgG to/from FcRn are pH dependent. Studies with mutant variants of wild-type IgG have clearly shown that a balance between binding at pH 6 and 7.4 is important for optimization of pharmacokinetic behavior (Deng et al, 2010(Deng et al, , 2012Datta-Mannan et al, 2012).…”

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confidence: 99%

“…Increased affinity of mAbs to FcRn at pH 6.0 was associated with greater s.c. bioavailability, whereas an increased affinity at pH 7.4 led to a decrease in s.c. absorption in mice (Deng et al, 2010(Deng et al, , 2012. In contrast, no definitive effect of altering FcRn affinity on s.c. bioavailability was found for a series of IgG4 variants in cynomolgus monkeys (Datta-Mannan et al, 2012).…”

Section: Introductionmentioning

confidence: 96%

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Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Kagan

Mager

2012

Drug Metab Dispos

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Absorption of monoclonal antibodies (mAbs) after s.c. injection results from the interplay among several kinetic processes. The aims of this study were to investigate the absorption mechanisms of rituximab in rats by using slow s.c. infusion and coadministration with nonspecific IgG or hyaluronidase, and to evaluate the predictive performance of the pharmacokinetic model previously developed to describe the nonlinear absorption behavior of mAbs. Rituximab serum concentrations were measured after s.c. coadministration with nonspecific IgG and hyaluronidase to rats. Several dose levels and different injection sites were evaluated. For the back site, 6.5-and 2.6-fold decreases in the area under the concentration-time curve were obtained after coadministration with IgG for 1 and 10 mg/kg doses compared with administration of rituximab alone. For the abdomen, only a minor reduction in concentrations was observed. Hyaluronidase increased the rate of s.c. absorption and the bioavailability (1.9-and 1.6-fold for the back and the abdomen injection of 10 mg/kg). Our previously established pharmacokinetic model provided excellent predictions of the effect of nonspecific IgG on rituximab absorption. In conclusion, the magnitude of the effect of absorption modifiers is dependent on the site of injection and the dose level of rituximab. Pharmacokinetic profiles further support the hypothesis that neonatal Fc receptormediated transport is a major determinant of s.c. absorption of mAbs.

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confidence: 99%

Section: Introductionmentioning

confidence: 96%

Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Kagan

Mager

2012

Drug Metab Dispos

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“…As such, a number of laboratories have examined the effects of modulating the interaction of mAbs with the FcRn in an effort to advance improvements in mAb PK. [10][11][12][13][14][15][16][17][18][19] Some disclosures have reported success in reducing IgG clearance via Fc engineering strategies that improve the FcRn binding properties of mAbs. 12,20,21 mAbs targeting low expression soluble antigens are more likely to have their kinetics dictated by the non-specific FcRn pathway, and, as such, the influence of Fc engineering to improve FcRn interaction and pharmacokinetics is most clearly demonstrated in in vivo systems with low/no endogenous antigen.…”

Section: Introductionmentioning

confidence: 99%

The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies

Datta‐Mannan

Witcher

et al. 2015

mAbs

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The application of protein engineering technologies toward successfully improving antibody pharmacokinetics has been challenging due to the multiplicity of biochemical factors that influence monoclonal antibody (mAb) disposition in vivo. Physiological factors including interactions with the neonatal Fc receptor (FcRn) and specific antigen binding properties of mAbs, along with biophysical properties of the mAbs themselves play a critical role. It has become evident that applying an integrated approach to understand the relative contribution of these factors is critical to rationally guide and apply engineering strategies to optimize mAb pharmacokinetics. The study presented here evaluated the influence of unintended non-specific interactions on the disposition of mAbs whose clearance rates are governed predominantly by either non-specific (FcRn) or target-mediated processes. The pharmacokinetics of 8 mAbs representing a diverse range of these properties was evaluated in cynomolgus monkeys. Results revealed complementarity-determining region (CDR) charge patch engineering to decrease charge-related non-specific binding can have a significant impact on improving the clearance. In contrast, the influence of enhanced in vitro FcRn binding was mixed, and related to both the strength of charge interaction and the general mechanism predominant in governing the clearance of the particular mAb. Overall, improved pharmacokinetics through enhanced FcRn interactions were apparent for a CDR charge-patch normalized mAb which was affected by non-specific clearance. The findings in this report are an important demonstration that mAb pharmacokinetics requires optimization on a case-bycase basis to improve the design of molecules with increased therapeutic application.

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“…Likewise, Gurbaxani et al (2006) were unable to directly correlate FcRn binding affinity to the pharmacokinetics of a number of IgGs in mice. The quantitative correlation of FcRn affinity improvement with in vivo pharmacokinetic parameters has also been ambiguous in primate studies of engineered mAbs (Deng et al, 2010;Datta-Mannan et al, 2012). Deng et al (2010) showed an anti-tumor necrosis factor-␣ mAb Fc variant (N434H) with ϳ3-fold higher FcRn affinity at pH 6 had similar pharmacokinetics in cynomolgus monkeys compared with a lower receptor affinity variant constructed on the same mAb backbone (N434A), although these findings may have been compromised by anti-drug antibodies.…”

Section: Introductionmentioning

confidence: 99%