Increasing the serum persistence of an IgG fragment by random mutagenesis

Gheţie, Victor; Попов, Сергей Витальевич; Borvak, Jozef; Radu, Caius G.; Matesoi, Diana; Medesan, Corneliu; Ober, Raimund J.; Ward, E. Sally

doi:10.1038/nbt0797-637

Cited by 228 publications

(175 citation statements)

References 33 publications

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“…The K D values obtained were 8.5 Ϯ 0.5 ϫ 10 Ϫ9 M (K D1 ) and 450.0 Ϯ 65.0 ϫ 10 Ϫ9 M (K D2 ). This is in accordance with values obtained by others with immobilized murine receptor (19).…”

Section: Resultssupporting

confidence: 82%

Cross-species Binding Analyses of Mouse and Human Neonatal Fc Receptor Show Dramatic Differences in Immunoglobulin G and Albumin Binding

Andersen

Daba

Berntzen

et al. 2010

Journal of Biological Chemistry

178

175

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The neonatal Fc receptor (FcRn) regulates the serum half-life of both IgG and albumin through a pH-dependent mechanism that involves salvage from intracellular degradation. WT bound strongly to human IgG1. The latter pair also interacted at physiological pH with calculated affinity in the micromolar range. In all cases, binding of albumin and IgG from either species to both receptors were additive. Cross-species albumin binding differences could partly be explained by nonconserved amino acids found within the ␣2-domain of the receptor. Such distinct cross-species FcRn binding differences must be taken into consideration when IgG-and albumin-based therapeutics and diagnostics are evaluated in rodents for their pharmacokinetics.

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Section: Resultssupporting

confidence: 82%

Cross-species Binding Analyses of Mouse and Human Neonatal Fc Receptor Show Dramatic Differences in Immunoglobulin G and Albumin Binding

Andersen

Daba

Berntzen

et al. 2010

Journal of Biological Chemistry

178

175

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show abstract

“…were among the earliest to propose that the half-life of antibodies could be extended through modification of the Fc domain to promote FcRn interaction, and they demonstrated that enhancing the binding of a mouse IgG1-derived Fc fragment to mouse FcRn at pH 6.0 by 3.5-fold increased the serum persistence of the antibody approximately 1.6-fold. 9 …”

Section: Introductionmentioning

confidence: 99%

Extending human IgG half-life using structure-guided design

Booth

Ramakrishnan

Narayan

et al. 2018

mAbs

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Engineering of antibodies for improved pharmacokinetics through enhanced binding to the neonatal Fc receptor (FcRn) has been demonstrated in transgenic mice, non-human primates and humans. Traditionally, such approaches have largely relied on random mutagenesis and display formats, which fail to address related critical attributes of the antibody, such as effector functions or biophysical stability. We have developed a structure- and network-based framework to interrogate the engagement of IgG with multiple Fc receptors (FcRn, C1q, TRIM21, FcγRI, FcγRIIa/b, FcγRIIIa) simultaneously. Using this framework, we identified features that govern Fc-FcRn interactions and identified multiple distinct pathways for enhancing FcRn binding in a pH-specific manner. Network analysis provided a novel lens to study the allosteric impact of half-life-enhancing Fc mutations on FcγR engagement, which occurs distal to the FcRn binding site. Applying these principles, we engineered a panel of unique Fc variants that enhance FcRn binding while maintaining robust biophysical properties and wild type-like binding to activating receptors. An antibody harboring representative Fc designs demonstrates a half-life improvement of > 9 fold in transgenic mice and > 3.5 fold in cynomolgus monkeys, and maintains robust effector functions such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.

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“…Fusion of the IgG Fc region to cytokines has been used to extend its half-life, since the average half-life of IgG is approximately 21 days due to neonatal Fc receptor (FcRn)-mediated transcytosis and endosomal recycling [11][12][13]. It was reported that fusion of either the lytic or nonlytic IgG2a Fc fragment to cytokines (e.g.…”

Section: Introductionmentioning

confidence: 99%

Marked enhancement of antigen‐specific T‐cell responses by IL‐7‐fused nonlytic, but not lytic, Fc as a genetic adjuvant

et al. 2010

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IL-7 plays a crucial role in the homeostatic proliferation, differentiation and survival of T cells, as well as in the survival and proliferation of precursor B cells. Here, we demonstrated that utilizing nonlytic Fc-fused IL-7 (IL-7-Fc m ) as a genetic adjuvant significantly enhanced not only CD4 1 but also CD8 1 T-cell responses by E7 DNA immunization, in addition to improving protection against TC-1-induced tumors in comparison to IL-7 alone. Similar results were obtained in OT-1 adoptive transfer experiments with OVA DNA injection, suggesting independence from antigenic nature and experimental conditions. In particular, the increased frequency of CD8 1 T cells was mainly due to enhanced T-cell proliferation in T-cell priming, and not to decreased cellular apoptosis. Interestingly, the enhanced adjuvant effect was not seen in the co-delivery of lytic Fc-fused IL-7 (IL-7-Fc) which increases T-cell apoptosis as well as T-cell proliferation, suggesting that the T-cell proliferative effect may be neutralized by T-cell apoptosis. Thus, our findings suggest that nonlytic Fc, in contrast to lytic Fc, fusion to cytokines may provide an insight in designing a potent genetic adjuvant for inducing CD4 1 and CD8 1 T-cell responses.

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Increasing the serum persistence of an IgG fragment by random mutagenesis

Cited by 228 publications

References 33 publications

Cross-species Binding Analyses of Mouse and Human Neonatal Fc Receptor Show Dramatic Differences in Immunoglobulin G and Albumin Binding

Cross-species Binding Analyses of Mouse and Human Neonatal Fc Receptor Show Dramatic Differences in Immunoglobulin G and Albumin Binding

Extending human IgG half-life using structure-guided design

Marked enhancement of antigen‐specific T‐cell responses by IL‐7‐fused nonlytic, but not lytic, Fc as a genetic adjuvant

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