Plasmonic measurements of monoclonal antibody self‐association using self‐interaction nanoparticle spectroscopy

Jayaraman, Jayapriya; Wu, Jugang; Brunelle, Molly C.; Cruz, Anna Marie M.; Goldberg, Deborah S.; Lobo, Brian A.; Shah, Ambarish; Tessier, Peter M.

doi:10.1002/bit.25221

Cited by 32 publications

(36 citation statements)

References 29 publications

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“…The intermolecular interactions are considered to be attractive if k D < ¡5.1 mL per gm, otherwise they are considered repulsive. However, Tessier and coworkers 37 suggested a cutoff at approximately ¡8 mL per gm. Note that these cutoff values depend upon peculiarities of antibody molecules, and are expected to change from molecule to molecule.…”

Section: Theoretical Foundations and Experimentally Measurable Quantimentioning

confidence: 99%

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Tomar

Kumar

Singh

et al. 2016

mAbs

160

145

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Effective translation of breakthrough discoveries into innovative products in the clinic requires proactive mitigation or elimination of several drug development challenges. These challenges can vary depending upon the type of drug molecule. In the case of therapeutic antibody candidates, a commonly encountered challenge is high viscosity of the concentrated antibody solutions. Concentration-dependent viscosity behaviors of mAbs and other biologic entities may depend on pairwise and higher-order intermolecular interactions, non-native aggregation, and concentration-dependent fluctuations of various antibody regions. This article reviews our current understanding of molecular origins of viscosity behaviors of antibody solutions. We discuss general strategies and guidelines to select low viscosity candidates or optimize lead candidates for lower viscosity at early drug discovery stages. Moreover, strategies for formulation optimization and excipient design are also presented for candidates already in advanced product development stages. Potential future directions for research in this field are also explored.

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Section: Theoretical Foundations and Experimentally Measurable Quantimentioning

confidence: 99%

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Tomar

Kumar

Singh

et al. 2016

mAbs

160

145

View full text Add to dashboard Cite

show abstract

“…These included 3 cross-interaction related assays (cross interaction chromatography (CIC), 31 baculovirus ELISA, 24 and polyspecificity reagent (PSR) binding assay), 32 as well as one self-interaction related assay (affinity capture self-interaction nanoparticle spectroscopy (AC-SINS)). 33,34 The CIC plots for the 2 antibodies are shown in Fig. 1 and assay results are summarized in Table 1.…”

Section: Application Of Early Stage Developability Assaysmentioning

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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“…For monoclonal antibodies, these properties include high-level expression, high solubility, covalent integrity, conformational and colloidal stability, low polyspecificity, and low immunogenicity. The high cost of failing any of these criteria at a late stage in drug development has led to considerable efforts at predicting developability on the basis of sequence motifs and experimentally determined biophysical properties (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Biophysical properties of the clinical-stage antibody landscape

Jain

Sun

Durand

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

492

824

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Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of "developability." Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotypematched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for future antibody drug candidates.monoclonal antibody | developability | biophysical properties | manufacturability | nonspecificity T arget binding is the predominant first concern in development of any drug. However, once a lead molecule attains the desired potency of biological modification, a suite of characteristics termed "developability" assumes critical importance. For monoclonal antibodies, these properties include high-level expression, high solubility, covalent integrity, conformational and colloidal stability, low polyspecificity, and low immunogenicity. The high cost of failing any of these criteria at a late stage in drug development has led to considerable efforts at predicting developability on the basis of sequence motifs and experimentally determined biophysical properties (1-15).In a landmark study of small-molecule drugs over 2,000 molecules with United States Adopted Names (USAN) designations and known to have oral availability were collected and computationally analyzed (16). A simple set of thresholds, encapsulated as the "Lipinski rule of fives," was formulated and has been used by many to prioritize small molecules for entry into clinical development. To date, analogous guiding principles for antibody drugs have not emerged-we therefore endeavor here to do so. By analogy to the Lipinski effort, we first collected the sequences of antibodies that had reached at least phase-2 trials and had USAN or WHO International Nonproprietary Names (INN) designations (137 in total as of the start of this project). As a common basis for comparison of intrinsic variable domain phenotypes we expressed each antibody as the human IgG1 isotype and formulated them in simple Hepes-buffered saline. Each antibody was then subjected to a battery of 12 different biophysical assays in common use for developability assessment.Unexpectedly, for many of the measures the distribution of values was not symmetrically Gaussian, but instead was lon...

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Plasmonic measurements of monoclonal antibody self‐association using self‐interaction nanoparticle spectroscopy

Cited by 32 publications

References 29 publications

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

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

Biophysical properties of the clinical-stage antibody landscape

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