The Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment with TNF-alpha Antagonist

Vaisman-Mentesh, A.; Rosenstein, S.; Yavzori, M.; Dror, Y.; Fudim, E.; Ungar, B.; Kopylov, U.; Picard, O.; Kigel, A.; Ben-Horin, S.; Benhar, I.; Wine, Y.

doi:10.1101/509489

bioRxiv · 10.1101/509489

The Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment with TNF-alpha Antagonist

Vaisman-Mentesh, A.·Rosenstein, S.·Yavzori, M.·Dror, Y.·Fudim, E.·Ungar, B.·Kopylov, U.·Picard, O.·Kigel, A.·Ben-Horin, S.·Benhar, I.·Wine, Y.

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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 drugs 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 TNF 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 {lambda} light chain in a subset of neutralizing ADA. Moreover, we show that administration of TNF 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.

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Vaisman-Mentesh, A., Rosenstein, S., Yavzori, M., Dror, Y., Fudim, E., Ungar, B., Kopylov, U., Picard, O., Kigel, A., Ben-Horin, S., Benhar, I., Wine, Y.. 2019-01-02. The Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment with TNF-alpha Antagonist. https://doi.org/10.1101/509489

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