Effects of altered FcγR binding on antibody pharmacokinetics in cynomolgus monkeys
| العنوان: | Effects of altered FcγR binding on antibody pharmacokinetics in cynomolgus monkeys |
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| المؤلفون: | Robert F. Kelley, Laura DeForge, Kyra J. Cowan, Maya Leabman, Y. Gloria Meng, Suhasini Iyer |
| المصدر: | mAbs. 5:896-903 |
| بيانات النشر: | Informa UK Limited, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Glycosylation, Immunology, Enzyme-Linked Immunosorbent Assay, Receptors, Fc, Plasma protein binding, Pharmacology, chemistry.chemical_compound, Cricetinae, Report, Animals, Immunology and Allergy, Receptor, chemistry.chemical_classification, Dose-Response Relationship, Drug, biology, Chinese hamster ovary cell, Wild type, Antibodies, Monoclonal, Genetic Variation, Molecular biology, Fragment crystallizable region, Amino acid, Macaca fascicularis, chemistry, biology.protein, Antibody, Protein Binding |
| الوصف: | Antibody interactions with Fcγ receptors (FcγRs), like FcγRIIIA, play a critical role in mediating antibody effector functions and thereby contribute significantly to the biologic and therapeutic activity of antibodies. Over the past decade, considerable work has been directed towards production of antibodies with altered binding affinity to FcγRs and evaluation of how the alterations modulate their therapeutic activity. This has been achieved by altering glycosylation status at N297 or by engineering modifications in the crystallizable fragment (Fc) region. While the effects of these modifications on biologic activity and efficacy have been examined, few studies have been conducted to understand their effect on antibody pharmacokinetics (PK). We present here a retrospective analysis in which we characterize the PK of three antibody variants with decreased FcγR binding affinity caused by amino acid substitutions in the Fc region (N297A, N297G, and L234A/L235A) and three antibody variants with increased FcγRIIIA binding affinity caused by afucosylation at N297, and compare their PK to corresponding wild type antibody PK in cynomolgus monkeys. For all antibodies, PK was examined at a dose that was known to be in the linear range. Since production of the N297A and N297G variants in Chinese hamster ovary cells results in aglycosylated antibodies that do not bind to FcγRs, we also examined the effect of expression of an aglycosylated antibody, without sequence change(s), in E. coli. All the variants demonstrated similar PK compared with that of the wild type antibodies, suggesting that, for the six antibodies presented here, altered FcγR binding affinity does not affect PK. |
| تدمد: | 1942-0870 1942-0862 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cdd72f541ae11adc6505fe61a2bd0922 https://doi.org/10.4161/mabs.26436 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....cdd72f541ae11adc6505fe61a2bd0922 |
| قاعدة البيانات: | OpenAIRE |
PDF full text from Publisher | تدمد: | 19420870 19420862 |
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