Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNFα Antagonists

Anna Vaisman-Mentesh, Shai Rosenstein, Miri Yavzori, Yael Dror, Ella Fudim, Bella Ungar, Uri Kopylov, Orit Picard, Aya Kigel, Shomron Ben-Horin, Itai Benhar, Yariv Wine*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Drugs formulated from monoclonal antibodies (mAbs) are clinically effective in various diseases. Repeated administration of mAbs, however, elicits an immune response in the form of anti-drug-antibodies (ADA), thereby reducing the drug's efficacy. Notwithstanding their importance, the molecular landscape of ADA and the mechanisms involved in their formation are not fully understood. Using a newly developed quantitative bio-immunoassay, we found that ADA concentrations specific to TNFα antagonists can exceed extreme concentrations of 1 mg/ml with a wide range of neutralization capacity. Our data further suggest a preferential use of the λ light chain in a subset of neutralizing ADA. Moreover, we show that administration of TNFα antagonists result in a vaccine-like response whereby ADA formation is governed by the extrafollicular T cell-independent immune response. Our bio-immunoassay coupled with insights on the nature of the immune response can be leveraged to improve mAb immunogenicity assessment and facilitate improvement in therapeutic intervention strategies.

Original languageEnglish
Article number2921
JournalFrontiers in Immunology
Volume10
DOIs
StatePublished - 18 Dec 2019

Funding

FundersFunder number
Department of Molecular Biology
Umea University
Bloom's Syndrome Foundation
United States-Israel Binational Science Foundation2017359

    Keywords

    • anti-drug antibodies
    • antibody repertoire
    • biologics
    • high-throughput sequencing
    • immunogenicity
    • monoclonal antibody
    • next generation sequencing
    • proteomics

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