Immunogenicity of MAbs in Non-human Primates During Nonclinical Safety Assessment

Overview

Journal MAbs

Specialty Allergy & Immunology

Date 2013 Aug 9

PMID 23924803

Citations 54

Authors

Peter J K van Meer

Marlous Kooijman

Vera Brinks

Christine C Gispen-de Wied

Beatriz Silva-Lima

Ellen H M Moors

Huub Schellekens

Affiliations

Soon will be listed here.

Abstract

The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.

Citing Articles

NI-3201 Is a Bispecific Antibody Mediating PD-L1-Dependent CD28 Co-stimulation on T Cells for Enhanced Tumor Control.

Majocchi S, Lloveras P, Nouveau L, Legrand M, Viandier A, Malinge P Cancer Immunol Res. 2025; 13(3):365-383.

PMID: 39760515 PMC: 11876958. DOI: 10.1158/2326-6066.CIR-24-0298.

Immunogenicity risk assessment and mitigation for engineered antibody and protein therapeutics.

Carter P, Quarmby V Nat Rev Drug Discov. 2024; 23(12):898-913.

PMID: 39424922 DOI: 10.1038/s41573-024-01051-x.

A Minimal PBPK/PD Model with Expansion-Enhanced Target-Mediated Drug Disposition to Support a First-in-Human Clinical Study Design for a FLT3L-Fc Molecule.

Hosseini I, Fleisher B, Getz J, Decalf J, Kwong M, Ovacik M Pharmaceutics. 2024; 16(5).

PMID: 38794321 PMC: 11125320. DOI: 10.3390/pharmaceutics16050660.

Targeting CEACAM5-positive solid tumors using NILK-2401, a novel CEACAM5xCD47 κλ bispecific antibody.

Seckinger A, Buatois V, Moine V, Daubeuf B, Richard F, Chatel L Front Immunol. 2024; 15:1378813.

PMID: 38720892 PMC: 11076849. DOI: 10.3389/fimmu.2024.1378813.

HPN328, a Trispecific T Cell-Activating Protein Construct Targeting DLL3-Expressing Solid Tumors.

Molloy M, Aaron W, Barath M, Bush M, Callihan E, Carlin K Mol Cancer Ther. 2024; 23(9):1294-1304.

PMID: 38670552 PMC: 11372363. DOI: 10.1158/1535-7163.MCT-23-0524.

References

Brinks V, Jiskoot W, Schellekens H . Immunogenicity of therapeutic proteins: the use of animal models. Pharm Res. 2011; 28(10):2379-85. PMC: 3170476. DOI: 10.1007/s11095-011-0523-5. View

Isaacs J, Manna V, Rapson N, Bulpitt K, Hazleman B, Matteson E . CAMPATH-1H in rheumatoid arthritis--an intravenous dose-ranging study. Br J Rheumatol. 1996; 35(3):231-40. DOI: 10.1093/rheumatology/35.3.231. View

Schellekens H . The immunogenicity of therapeutic proteins. Discov Med. 2010; 9(49):560-4. View

Koren E, De Groot A, Jawa V, Beck K, Boone T, Rivera D . Clinical validation of the "in silico" prediction of immunogenicity of a human recombinant therapeutic protein. Clin Immunol. 2007; 124(1):26-32. DOI: 10.1016/j.clim.2007.03.544. View

Wadhwa M, Thorpe R . Strategies and assays for the assessment of unwanted immunogenicity. J Immunotoxicol. 2008; 3(3):115-21. DOI: 10.1080/15476910600845534. View

Baldrick P . Safety evaluation of biological drugs: what are toxicology studies in primates telling us?. Regul Toxicol Pharmacol. 2010; 59(2):227-36. DOI: 10.1016/j.yrtph.2010.10.005. View

Thullier P, Chahboun S, Pelat T . A comparison of human and macaque (Macaca mulatta) immunoglobulin germline V regions and its implications for antibody engineering. MAbs. 2010; 2(5):528-38. PMC: 2958574. DOI: 10.4161/mabs.2.5.12545. View

Kessler M, Goldsmith D, Schellekens H . Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant. 2006; 21 Suppl 5:v9-12. DOI: 10.1093/ndt/gfl476. View

Koren E, Zuckerman L, Mire-Sluis A . Immune responses to therapeutic proteins in humans--clinical significance, assessment and prediction. Curr Pharm Biotechnol. 2002; 3(4):349-60. DOI: 10.2174/1389201023378175. View

10.

Getts D, Getts M, P McCarthy D, Chastain E, Miller S . Have we overestimated the benefit of human(ized) antibodies?. MAbs. 2010; 2(6):682-94. PMC: 3011222. DOI: 10.4161/mabs.2.6.13601. View

11.

Bartelds G, Krieckaert C, Nurmohamed M, van Schouwenburg P, Lems W, Twisk J . Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011; 305(14):1460-8. DOI: 10.1001/jama.2011.406. View

12.

Schellekens H . Factors influencing the immunogenicity of therapeutic proteins. Nephrol Dial Transplant. 2005; 20 Suppl 6:vi3-9. DOI: 10.1093/ndt/gfh1092. View

13.

Harding F, Stickler M, Razo J, DuBridge R . The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010; 2(3):256-65. PMC: 2881252. DOI: 10.4161/mabs.2.3.11641. View

14.

Chapman K, Pullen N, Coney L, Dempster M, Andrews L, Bajramovic J . Preclinical development of monoclonal antibodies: considerations for the use of non-human primates. MAbs. 2010; 1(5):505-16. PMC: 2759500. DOI: 10.4161/mabs.1.5.9676. View

15.

De Groot A, Knopp P, Martin W . De-immunization of therapeutic proteins by T-cell epitope modification. Dev Biol (Basel). 2005; 122:171-94. View

16.

Ponce R, Abad L, Amaravadi L, Gelzleichter T, Gore E, Green J . Immunogenicity of biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies. Regul Toxicol Pharmacol. 2009; 54(2):164-82. DOI: 10.1016/j.yrtph.2009.03.012. View

17.

Brennan F, Morton L, Spindeldreher S, Kiessling A, Allenspach R, Hey A . Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. MAbs. 2010; 2(3):233-55. PMC: 2881251. DOI: 10.4161/mabs.2.3.11782. View

18.

Gorovits B . Antidrug antibody assay validation: industry survey results. AAPS J. 2009; 11(1):133-8. PMC: 2664891. DOI: 10.1208/s12248-009-9091-6. View

19.

Hwang W, Foote J . Immunogenicity of engineered antibodies. Methods. 2005; 36(1):3-10. DOI: 10.1016/j.ymeth.2005.01.001. View

20.

Gaitonde P, Balu-Iyer S . In vitro immunogenicity risk assessment of therapeutic proteins in preclinical setting. Methods Mol Biol. 2011; 716:267-80. PMC: 3058249. DOI: 10.1007/978-1-61779-012-6_16. View