Antibodies to watch in 2014

Reichert, Janice M.

doi:10.4161/mabs.27333

Cited by 92 publications

(53 citation statements)

References 28 publications

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“…1 While inflammatory disorders and cancer remain the main targets, mAb therapies are being considered for a variety of new indications and an increasing number of mAbs are receiving orphan drug status. [2][3][4] To meet the demand for mAbs to new targets and maintain competitiveness within the sector, novel discovery platforms and antibody engineering are required to develop the next generation of mAbs. 3,[5][6][7] The pharmacokinetic (PK) properties of a mAb is widely regarded as a critical parameter to optimize for the successful production of more effective, safer and cheaper mAb therapeutics.…”

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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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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“…[1][2][3][4] However, their monospecific configuration also restricts overall therapeutic potential owing to the simultaneous deregulation of several mediators in many diseases. [5][6][7] Bispecific antibodies (bsAb) enable simultaneous engagement of 2 targets and offer the potential of greater therapeutic efficacy while overcoming major escape mechanisms seen in mono-targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

Insights into the molecular basis of a bispecific antibody's target selectivity

Mazor¹,

Hansen²,

Yang³

et al. 2015

mAbs

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“…39 Most of the antibodies that are currently in Phase 3 clinical trials are either humanized or have been derived from transgenic animals. 40 Therefore, our strategy was to work under physiologically relevant conditions and to take advantage of the in vivo selection process to generate high-affinity antibodies. Table 6.…”

Section: Discussionmentioning

confidence: 99%

“…To humanize the heavy chain, 11 V H framework positions (20,24,37,38,40,48,67,68,70,95, and 98) mostly based on their proximity to the CDRs were evaluated. In addition, one potential deamidation site ("NT") in H-CDR1 (Chothia), N27, was selected for mutagenesis to a glycine (G), phenylalanine (F) or tyrosine (Y) (common human germ-line residues at this position) to determine if the potential deamidation site could be removed.…”

Section: ¡1mentioning

confidence: 99%

Selective targeting of the IL23 pathway: Generation and characterization of a novel high-affinity humanized anti-IL23A antibody

Singh

Kroe‐Barrett

Canada

et al. 2015

mAbs

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(2015) Selective targeting of the IL23 pathway: Generation and characterization of a novel high-affinity humanized anti-IL23A antibody, mAbs, 7:4, 778-791, DOI: 10.1080DOI: 10. /19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 Herein, we describe the generation and characterization of BI 655066, a novel, highly potent neutralizing antiinterleukin-23 (IL23) monoclonal antibody in clinical development for autoimmune conditions, including psoriasis and Crohn's disease. IL23 is a key driver of the differentiation, maintenance, and activity of a number of immune cell subsets, including T helper 17 (Th17) cells, which are believed to mediate the pathogenesis of several immunemediated disorders. Thus, IL23 neutralization is an attractive therapeutic approach. Designing an antibody for clinical activity and convenience for the patient requires certain properties, such as high affinity, specificity, and solubility. These properties were achieved by directed design of the immunization, lead identification, and humanization procedures. Favorable substance and pharmacokinetic properties were established by biophysical assessments and studies in cynomolgus monkeys.

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Antibodies to watch in 2014

Cited by 92 publications

References 28 publications

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

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

Insights into the molecular basis of a bispecific antibody's target selectivity

Selective targeting of the IL23 pathway: Generation and characterization of a novel high-affinity humanized anti-IL23A antibody

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