PT  - JOURNAL ARTICLE
AU  - Anna Vaisman-Mentesh
AU  - Shai Rosenstein
AU  - Miri Yavzori
AU  - Yael Dror
AU  - Ella Fudim
AU  - Bella Ungar
AU  - Uri Kopylov
AU  - Orit Picard
AU  - Aya Kigel
AU  - Shomron Ben-Horin
AU  - Itai Benhar
AU  - Yariv Wine
TI  - Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment with TNFα Antagonists
AID  - 10.1101/509489
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 509489
4099  - http://biorxiv.org/content/early/2019/12/11/509489.short
4100  - http://biorxiv.org/content/early/2019/12/11/509489.full
AB  - 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.