PK/PD analysis of a novel pH-dependent antigen-binding antibody using a dynamic antibody–antigen binding model

Haraya, Kenta; Tachibana, Tatsuhiko; Iwayanagi, Yuki; Maeda, Atsuhiko; Ozeki, Kazuhisa; Nezu, Jun-ichi; Ishigai, Masaki; Igawa, Tomoyuki

doi:10.1016/j.dmpk.2015.12.007

Cited by 9 publications

(10 citation statements)

References 41 publications

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“…In order to identify mutations that improve the C5-binding property, we expressed more than 1,000 antibody variants, each containing a single mutation through the COSMO approach, as described in Materials & Methods. In this way, we identified mutations that increased the association rate, which are crucial for our desired pH-dependent C5-binding antibody [16] but are difficult to identify by simple panning methods from display libraries. In parallel, we also identified mutations that did not affect the C5-binding property and could therefore be useful for further antibody engineering, such as surface-charge engineering, improving stability, and reducing immunogenicity.…”

Section: Resultsmentioning

confidence: 99%

Antibody engineering to generate SKY59, a long-acting anti-C5 recycling antibody

Sampei¹,

Haraya²,

Tachibana³

et al. 2018

PLoS ONE

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Modulating the complement system is a promising strategy in drug discovery for disorders with uncontrolled complement activation. Although some of these disorders can be effectively treated with an antibody that inhibits complement C5, the high plasma concentration of C5 requires a huge dosage and frequent intravenous administration. Moreover, a conventional anti-C5 antibody can cause C5 to accumulate in plasma by reducing C5 clearance when C5 forms an immune complex (IC) with the antibody, which can be salvaged from endosomal vesicles by neonatal Fc receptor (FcRn)-mediated recycling. In order to neutralize the increased C5, an even higher dosage of the antibody would be required. This antigen accumulation can be suppressed by giving the antibody a pH-dependent C5-binding property so that C5 is released from the antibody in the acidic endosome and then trafficked to the lysosome for degradation, while the C5-free antibody returns back to plasma. We recently demonstrated that a pH-dependent C5-binding antibody, SKY59, exhibited long-lasting neutralization of C5 in cynomolgus monkeys, showing potential for subcutaneous delivery or less frequent administration. Here we report the details of the antibody engineering involved in generating SKY59, from humanizing a rabbit antibody to improving the C5-binding property. Moreover, because the pH-dependent C5-binding antibodies that we first generated still accumulated C5, we hypothesized that the surface charges of the ICs partially contributed to a slow uptake rate of the C5–antibody ICs. This idea motivated us to engineer the surface charges of the antibody. Our surface-charge engineered antibody consequently exhibited a high capacity to sweep C5 and suppressed the C5 accumulation in vivo by accelerating the cycle of sweeping: uptake of ICs into cells, release of C5 from the antibody in endosomes, and salvage of the antigen-free antibody. Thus, our engineered anti-C5 antibody, SKY59, is expected to provide significant benefits for patients with complement-mediated disorders.

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Section: Resultsmentioning

confidence: 99%

Antibody engineering to generate SKY59, a long-acting anti-C5 recycling antibody

Sampei¹,

Haraya²,

Tachibana³

et al. 2018

PLoS ONE

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“…Next, we tested if our model could capture the benefit of a recycling antibody PH-IgG 1 in target suppression in comparison to its pH-independent counterpart NPH-IgG 1 . Both antibodies were co-injected with the human antigen hsIL6-R into hFcRn Tg32 homozygous transgenic mice (14). These two antibodies exhibited similar plasma profiles.…”

Section: Resultsmentioning

confidence: 99%

“…Prediction of hsIL6-R profiles in hFcRn transgenic mice was conducted similarly to the TNF-α case in humans. Since each antibody binds two hsIL6-R (14), the target concentration was divided by two in the model equations. Systemic clearance of free target was obtained from a pharmacokinetic study in healthy mice (8).…”

Section: Resultsmentioning

confidence: 99%

“…Pharmacokinetic data for mAbs are digitized from the literature using WebPlot Digitizer v3.11 (Austin, Tx): adalimumab (9) and infliximab(10) in rheumatoid arthritis (RA) patients, radiolabeled human IgG in a familial hypercatabolic hypoproteinemia patient (4)motavizumab and its YTE variant in healthy humans (11), B21m in hFcRn Tg32 homozygous transgenic mice at a dose of 2 mg/kg (12), bevacizumab and its Xtend variant in hFcRn Tg276 heterozygous transgenic mice at a dose of 2 mg/kg (13), and two human IgG1 mAbs against human soluble interleukin 6 receptor (hsIL6-R) in hFcRn Tg32 homozygous transgenic mice, one pH-independent (NPH-IgG1) and one pH-dependent (PH-IgG1) at a dose of 2 mg/kg (14). hsIL6-R was co-injected at a dose of 50 μg/kg (14). All antibodies and hsIL6-R were given intravenously.…”

Section: Methodsmentioning

confidence: 99%

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A Minimal Physiologically Based Pharmacokinetic Model with a Nested Endosome Compartment for Novel Engineered Antibodies

Yuan

Rode

Cao

2018

AAPS J

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We proposed here a minimal physiologically based pharmacokinetic (mPBPK) model for a group of novel engineered antibodies in mice and humans. These antibodies are designed with altered binding properties of their Fc domain with neonatal Fc receptor (FcRn) or the Fab domain with their cognate targets (recycling antibodies) in acidic endosomes. To enable simulations of such binding features in the change of antibody pharmacokinetics and its target suppression, we nested an endothelial endosome compartment in parallel with plasma compartment based on our previously established mPBPK model. The fluid-phase pinocytosis rate from plasma to endothelial endosomes was reflected by the clearance of antibodies in FcRn dysfunctional humans or FcRn-knockout mice. The endosomal recycling rate of FcRn-bound antibodies was calculated based on the reported endosomal transit time. The nonspecific catabolism in endosomes was fitted using pharmacokinetic data of a human wild-type IgG adalimumab in humans and B21M in human FcRn (hFcRn) transgenic mice. The developed model adequately predicted the pharmacokinetics of infliximab, motavizumab, and an Fc variant of motavizumab in humans and the pharmacokinetics of bevacizumab, an Fc variant of bevacizumab, and a recycling antibody PH-IgG and its non-pH dependent counterpart NPH-IgG in hFcRn transgenic mice. Our proposed model provides a platform for evaluation of the pharmacokinetics and disposition behaviors of Fc-engineered antibodies and recycling antibodies.

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“…To further interrogate the potential utility of the antigen sweeping mechanism to enhance target suppression, Haraya et al implemented a modified dynamic antibody-antigen binding target-mediated drug disposition model. 29 The model incorporated empirically-derived composite parameters that represented uptake clearance and differential recycling of antibody in the antibody-target complex. Although this model was able to capture the observed phenotype for the sweeping mechanism, the capacity of such a model to address pertinent questions related to a priori identification of optimal antibody properties was confounded by the model's simplicity.…”

Section: Discussionmentioning

confidence: 99%

Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn

Yang

Giragossian

Lásaro

et al. 2017

mAbs

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Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool to conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due to high target burden. However, the requirements for optimal binding kinetic framework and extent of pH dependence for these antibodies to maximize target clearance from circulation are not well understood. We have identified a series of naturally-occurring high affinity antibodies with pH-dependent target binding properties. By in vivo studies in cynomolgus monkeys, we show that pH-dependent binding to the target alone is not sufficient for effective target removal from circulation, but requires Fc mutations that increase antibody binding to FcRn. Affinity-enhanced pH-dependent FcRn binding that is double-digit nM at pH 7.4 and single-digit nM at pH 6 achieved maximal target reduction when combined with similar target binding affinities in reverse pH directions. Sustained target clearance below the baseline level was achieved 3 weeks after single-dose administration at 1.5 mg/kg. Using the experimentally derived mechanistic model, we demonstrate the essential kinetic interplay between target turnover and antibody pH-dependent binding during the FcRn recycling, and identify the key components for achieving maximal target clearance. These results bridge the demand for improved patient dosing convenience with the “know-how” of therapeutic modality by design.

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PK/PD analysis of a novel pH-dependent antigen-binding antibody using a dynamic antibody–antigen binding model

Cited by 9 publications

References 41 publications

Antibody engineering to generate SKY59, a long-acting anti-C5 recycling antibody

Antibody engineering to generate SKY59, a long-acting anti-C5 recycling antibody

A Minimal Physiologically Based Pharmacokinetic Model with a Nested Endosome Compartment for Novel Engineered Antibodies

Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn

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