Identification of Human IgG1 Variant with Enhanced FcRn Binding and Without Increased Binding to Rheumatoid Factor Autoantibody

Overview

Journal MAbs

Specialty Allergy & Immunology

Date 2017 Apr 8

PMID 28387635

Citations 13

Authors

Atsuhiko Maeda

Yuki Iwayanagi

Kenta Haraya

Tatsuhiko Tachibana

Genki Nakamura

Takeru Nambu

Keiko Esaki

Kunihiro Hattori

Tomoyuki Igawa

Affiliations

Soon will be listed here.

Abstract

Various studies have demonstrated that Fc engineering to enhance neonatal Fc receptor (FcRn) binding is effective for elongating half-life or increasing cellular uptake of IgG. A previous study has shown that a N434H mutation to enhance FcRn binding resulted in increased binding to rheumatoid factor (RF) autoantibody, which is not desirable for therapeutic use in autoimmune disease. In this study, we first showed that all the existing Fc variants with enhanced FcRn binding also show increased RF binding, and then identified specific mutations that could be introduced to those Fc variants to reduce the RF binding. Furthermore, we generated novel Fc variants that do not increase RF binding and show half-lives of 45 d in cynomolgus monkey, which is longer than those of previously reported Fc variants. In addition, we generated novel Fc variants with antigen sweeping activity that do not increase RF binding. We expect that these novel Fc variants will be useful as antibody therapeutics against autoimmune diseases.

Citing Articles

Beyond Recycling Antibodies: Crovalimab's Molecular Design Enables Four-Weekly Subcutaneous Injections for PNH Treatment.

Sampei Z, Haraya K, Gan S, Muraoka M, Hayasaka A, Fukuzawa T Int J Mol Sci. 2024; 25(21).

PMID: 39519232 PMC: 11546984. DOI: 10.3390/ijms252111679.

Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria.

Foss S, Sakya S, Aguinagalde L, Lustig M, Shaughnessy J, Cruz A Nat Commun. 2024; 15(1):2007.

PMID: 38453922 PMC: 10920689. DOI: 10.1038/s41467-024-46321-9.

Characterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease.

Okura Y, Ikawa-Teranishi Y, Mizoroki A, Takahashi N, Tsushima T, Irie M Nat Commun. 2023; 14(1):8502.

PMID: 38135691 PMC: 10746718. DOI: 10.1038/s41467-023-44083-4.

Complement Activation by an Anti-Dengue/Zika Antibody with Impaired Fcγ Receptor Binding Provides Strong Efficacy and Abrogates Risk of Antibody-Dependent Enhancement.

Sampei Z, Koo C, Teo F, Toh Y, Fukuzawa T, Gan S Antibodies (Basel). 2023; 12(2).

PMID: 37218902 PMC: 10204484. DOI: 10.3390/antib12020036.

Recent Advances in Translational Pharmacokinetics and Pharmacodynamics Prediction of Therapeutic Antibodies Using Modeling and Simulation.

Haraya K, Tsutsui H, Komori Y, Tachibana T Pharmaceuticals (Basel). 2022; 15(5).

PMID: 35631335 PMC: 9145563. DOI: 10.3390/ph15050508.

References

Yeung Y, Leabman M, Marvin J, Qiu J, Adams C, Lien S . Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J Immunol. 2009; 182(12):7663-71. DOI: 10.4049/jimmunol.0804182. View

Igawa T, Maeda A, Haraya K, Tachibana T, Iwayanagi Y, Mimoto F . Engineered monoclonal antibody with novel antigen-sweeping activity in vivo. PLoS One. 2013; 8(5):e63236. PMC: 3646756. DOI: 10.1371/journal.pone.0063236. View

MARTIN W, West Jr A, Gan L, Bjorkman P . Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol Cell. 2001; 7(4):867-77. DOI: 10.1016/s1097-2765(01)00230-1. View

Zalevsky J, Chamberlain A, Horton H, Karki S, Leung I, Sproule T . Enhanced antibody half-life improves in vivo activity. Nat Biotechnol. 2010; 28(2):157-9. PMC: 2855492. DOI: 10.1038/nbt.1601. View

Krishna M, Nadler S . Immunogenicity to Biotherapeutics - The Role of Anti-drug Immune Complexes. Front Immunol. 2016; 7:21. PMC: 4735944. DOI: 10.3389/fimmu.2016.00021. View

Robbie G, Criste R, DallAcqua W, Jensen K, Patel N, Losonsky G . A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. 2013; 57(12):6147-53. PMC: 3837853. DOI: 10.1128/AAC.01285-13. View

Corper A, Sohi M, Bonagura V, Steinitz M, Jefferis R, Feinstein A . Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody-antigen interaction. Nat Struct Biol. 1997; 4(5):374-81. DOI: 10.1038/nsb0597-374. View

Wu S, Luo J, ONeil K, Kang J, Lacy E, Canziani G . Structure-based engineering of a monoclonal antibody for improved solubility. Protein Eng Des Sel. 2010; 23(8):643-51. DOI: 10.1093/protein/gzq037. View

Hyakumura M, Walsh R, Thaysen-Andersen M, Kingston N, La M, Lu L . Modification of Asparagine-Linked Glycan Density for the Design of Hepatitis B Virus Virus-Like Particles with Enhanced Immunogenicity. J Virol. 2015; 89(22):11312-22. PMC: 4645671. DOI: 10.1128/JVI.01123-15. View

10.

Araujo J, Zocher M, Wallace K, Peng K, Fischer S . Increased rheumatoid factor interference observed during immunogenicity assessment of an Fc-engineered therapeutic antibody. J Pharm Biomed Anal. 2011; 55(5):1041-9. DOI: 10.1016/j.jpba.2011.03.008. View

11.

Laurent L, Anquetil F, Clavel C, Ndongo-Thiam N, Offer G, Miossec P . IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies. Ann Rheum Dis. 2014; 74(7):1425-31. DOI: 10.1136/annrheumdis-2013-204543. View

12.

Deng R, Loyet K, Lien S, Iyer S, DeForge L, Theil F . Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-{alpha} antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys. Drug Metab Dispos. 2010; 38(4):600-5. DOI: 10.1124/dmd.109.031310. View

13.

Datta-Mannan A, Chow C, Dickinson C, Driver D, Lu J, Witcher D . FcRn affinity-pharmacokinetic relationship of five human IgG4 antibodies engineered for improved in vitro FcRn binding properties in cynomolgus monkeys. Drug Metab Dispos. 2012; 40(8):1545-55. DOI: 10.1124/dmd.112.045864. View

14.

Jack Borrok M, Wu Y, Beyaz N, Yu X, Oganesyan V, DallAcqua W . pH-dependent binding engineering reveals an FcRn affinity threshold that governs IgG recycling. J Biol Chem. 2014; 290(7):4282-90. PMC: 4326836. DOI: 10.1074/jbc.M114.603712. View

15.

Tatarewicz S, Miller J, Swanson S, Moxness M . Rheumatoid factor interference in immunogenicity assays for human monoclonal antibody therapeutics. J Immunol Methods. 2010; 357(1-2):10-6. DOI: 10.1016/j.jim.2010.03.012. View

16.

Rashid A, Auchincloss Jr H, Sharon J . Comparison of GK1.5 and chimeric rat/mouse GK1.5 anti-CD4 antibodies for prolongation of skin allograft survival and suppression of alloantibody production in mice. J Immunol. 1992; 148(5):1382-8. View

17.

Suzuki S, Furuhashi M, Suganuma N . Additional N-glycosylation at Asn(13) rescues the human LHbeta-subunit from disulfide-linked aggregation. Mol Cell Endocrinol. 2000; 160(1-2):157-63. DOI: 10.1016/s0303-7207(99)00213-0. View

18.

Jones J, Shyu I, Newkirk M, Rigby W . A rheumatoid factor paradox: inhibition of rituximab effector function. Arthritis Res Ther. 2013; 15(1):R20. PMC: 3672827. DOI: 10.1186/ar4152. View

19.

Sasso E, Barber C, Nardella F, Yount W, Mannik M . Antigenic specificities of human monoclonal and polyclonal IgM rheumatoid factors. The C gamma 2-C gamma 3 interface region contains the major determinants. J Immunol. 1988; 140(9):3098-107. View

20.

West Jr A, Bjorkman P . Crystal structure and immunoglobulin G binding properties of the human major histocompatibility complex-related Fc receptor(,). Biochemistry. 2000; 39(32):9698-708. DOI: 10.1021/bi000749m. View