Anti-p40 Antibodies Ustekinumab and Briakinumab: Blockade of Interleukin-12 and Interleukin-23 in the Treatment of Psoriasis

Gandhi, Mona A.; Alwawi, Eihab; Gordon, Kenneth B.

doi:10.1016/j.sder.2010.02.001

Cited by 60 publications

(42 citation statements)

References 14 publications

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“…This provides a matched case in which all differences are target independent and driven solely by the variable region. Despite the similarity between the 2 candidates, in Phase 1 clinical trials ustekinumab had a median half-life of 21 days, comparable to most clinical mAbs, while the half-life of briakinumab was only 8 d. 28 To evaluate the causes for this large discrepancy in PK, we ran a wide range of early developability screening assays, revealing a strong increase in self-and cross-interaction tendency for briakinumab. This developability profile translates into increased clearance rates in both huFcRn transgenic and FcRn knockout mice, demonstrating an FcRn-independent mechanism for clearance driven by antibody nonspecificity.…”

Section: Introductionmentioning

confidence: 99%

Target-independent variable region mediated effects on antibody clearance can be FcRn independent

Kelly

Sun

et al. 2016

mAbs

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The importance of the neonatal Fc receptor (FcRn) in extending the serum half-life of monoclonal antibodies (mAbs) is well demonstrated, and has led to the development of multiple engineering approaches designed to alter Fc interactions with FcRn. Recent reports have additionally highlighted the effect of nonspecific interactions on antibody pharmacokinetics (PK), suggesting an FcRn-independent mechanism for mAb clearance. In this report we examine a case study of 2 anti-interleukin-12/23 antibodies, ustekinumab and briakinumab, which share the same target and Fc, but differ in variable region sequences. Ustekinumab displayed near baseline signal in a wide range of early stage developability assays for undesirable protein/protein interactions, while briakinumab showed significant propensity for self-and cross-interactions. This phenotypic difference correlates with faster clearance rates for briakinumab in both human FcRn transgenic and FcRn knockout mice. These findings support a dominant contribution for FcRn-independent clearance for antibodies with high nonspecificity, and highlight a key role for early stage developability screening to eliminate clones with such high nonspecific disposition PK.

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Section: Introductionmentioning

confidence: 99%

Target-independent variable region mediated effects on antibody clearance can be FcRn independent

Kelly

Sun

et al. 2016

mAbs

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“…25,56,57 This phenomenon explains why circulating IgGs with identical Fc regions can vary 2-3 fold in serum half-life even when the same antigen is targeted. [58][59][60] Despite the well-characterized mAb-FcRn interaction and its effect on in vivo half-life, several hurdles that limit the usefulness of this information in experimental testing still remain. For example, several studies have attempted to measure the mAbFcRn interaction in vitro and draw a correlation to in vivo halflife, but the results have been largely mixed.…”

Section: Introductionmentioning

confidence: 99%

A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life

Souders

Nelson²,

Wang

et al. 2015

mAbs

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Immunoglobulin G (IgG) has an unusually long serum half-life in comparison to proteins of a similar size. It is wellknown that this phenomenon is due to IgG's ability to bind the neonatal Fc receptor (FcRn) in a pH-dependent manner. FcRn binding properties can vary among IgGs, resulting in altered in vivo half-lives, and therefore it would be beneficial to accurately predict the FcRn binding properties of therapeutic IgG monoclonal antibodies (mAbs). Here we describe the development of an in vitro model capable of predicting the in vivo half-life of human IgG. Using a high-throughput biolayer interferometry (BLI) platform, the human FcRn association rate at acidic pH and subsequent dissociation rate at physiological pH was determined for 5 human IgG1 mAbs. Comparing the combined FcRn association and dissociation rates to the Phase 1 clinical study half-lives of the mAbs resulted in a strong correlation. The correlation was also verified in vivo using mice transgenic for human FcRn. The model was used to characterize various factors that may influence FcRn-mAb binding, including mAb variable region sequence differences and constant region glycosylation patterns. Results indicated that the complementarity-determining regions of the heavy chain significantly influence the mAb's FcRn binding properties, while the absence of glycosylation does not alter mAb-FcRn binding. Development of this high-throughput FcRn binding model could potentially predict the half-life of therapeutic IgGs and aid in selection of lead candidates while also serving as a screening tool for the development of mAbs with desired pharmacokinetic properties.

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“…Although many of the observed PK differences can be rationalized by the known target-mediated clearance mechanism commonly associated with mAbs targeting membrane-bound antigens (Mager, 2006), the reason for some of these discrepancies remains unknown. For example, the recently approved human anti-p40 antibody ustekinumab had a reported median half-life of 22 days (Zhu et al, 2009), whereas another similar anti-p40 antibody, briakinumab, only exhibited a half-life of 8 to 9 days (Gandhi et al, 2010). Of interest, a recent report showed that mAbs and Fc fusion proteins with the same Fc sequence can bind to FcRn differently, highlighting the potential importance of FcRn in regulating PK of therapeutic mAbs with wild-type Fc sequences (Suzuki et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Monoclonal Antibodies with Identical Fc Sequences Can Bind to FcRn Differentially with Pharmacokinetic Consequences

Wang

Lü²,

Fang³

et al. 2011

Drug Metab Dispos

153

181

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ABSTRACT:The neonatal Fc receptor (FcRn) is a key determinant of IgG homeostasis. It binds to the Fc domain of IgG in a strictly pH-dependent manner and protects IgG from lysosomal degradation. The impact of FcRn salvage pathway on IgG monoclonal antibody (mAb) pharmacokinetics (PK) has been well established. In this report, a set of mAbs with wild-type human Fc sequences but different Fab domains were used to examine the potential impact of Fab domain on in vitro FcRn binding and in vivo PK. We were surprised to find that mAbs with the same wild-type human Fc sequences but different Fab domains were shown to bind FcRn with considerable differences in both the binding at acidic pH and the dissociation at neutral pH, suggesting that the Fab domain may also have an impact on FcRn interaction. For these mAbs, no relationship between the FcRn binding affinity at acidic pH and in vivo PK was found. Instead, an apparent correlation between the in vitro FcRn dissociation at neutral pH and the in vivo PK in human FcRn mice, nonhuman primates and humans was observed. Our results suggested that the Fab domain of mAbs can affect their interaction with FcRn and thus their pharmacokinetic properties and that in vitro FcRn binding/dissociation assays can be a useful screening tool for pharmacokinetic assessment of mAbs with wildtype Fc sequences.

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Anti-p40 Antibodies Ustekinumab and Briakinumab: Blockade of Interleukin-12 and Interleukin-23 in the Treatment of Psoriasis

Cited by 60 publications

References 14 publications

Target-independent variable region mediated effects on antibody clearance can be FcRn independent

Target-independent variable region mediated effects on antibody clearance can be FcRn independent

A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life

Monoclonal Antibodies with Identical Fc Sequences Can Bind to FcRn Differentially with Pharmacokinetic Consequences

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