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Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation.

Abstract：

OBJECTIVES:Millions of patients worldwide are treated with therapeutic monoclonal antibodies. These biological therapeutics can be immunogenic, resulting in anti-drug antibody formation which leads to loss of response. Fully human biological agents, such as the anti-tumour necrosis factor α (anti-TNFα) antibody adalimumab, are considered to be weakly immunogenic, but anti-adalimumab antibodies (AAA) were recently detected in more than half of treated patients with rheumatoid arthritis (RA) within 28 weeks of treatment. A study was undertaken to determine the mechanism by which AAA lead to loss of response. METHODS:The specificity of the repertoire of AAA was investigated in a cohort of 50 AAA-positive RA patients. Inhibition experiments using TNFα and patient-derived anti-adalimumab monoclonal antibodies were performed. RESULTS:The antibody response against adalimumab is highly restricted: Fab fragments of a single monoclonal antibody specific for the idiotype of adalimumab inhibited 98.65% (25th-75th percentiles: 98.25-99.90) of the total anti-adalimumab reactivity in serum from 50 AAA-positive patients. The anti-adalimumab response was confined to the TNFα binding region of adalimumab, thereby neutralising its therapeutic efficacy. In line with this restricted specificity, small immune complexes were found in the circulation of AAA-forming patients. CONCLUSIONS:The humoral immune response against adalimumab is highly restricted and limited to the idiotype of the therapeutic antibody. All antibodies result in functional neutralisation of the drug, thereby providing a mechanism by which AAA formation leads to clinical non-response.

journal_name

Ann Rheum Dis

journal_title

Annals of the rheumatic diseases

authors

van Schouwenburg PA,van de Stadt LA,de Jong RN,van Buren EE,Kruithof S,de Groot E,Hart M,van Ham SM,Rispens T,Aarden L,Wolbink GJ,Wouters D

doi

10.1136/annrheumdis-2012-201445

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

104-9

issue

eissn

0003-4967

issn

1468-2060

pii

annrheumdis-2012-201445

journal_volume

pub_type

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Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation.