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Anti-drug antibodies may intrinsically be neutralizing

Antibodies towards therapeutic antibodies may be inherently neutralizing. That is what researchers of Sanquin Biologicals report in the Journal of Allergy and Clinical Immunology. Similar to the antibody responses evoked to TNF-inhibitors, they found that the immune response to natalizumab, is largely directed against the antigen binding site. This has implications for drug development and monitoring of clinical trials.

Recently, Karin van Schie of the group of Theo Rispens investigated the antibody repertoire in patients who mounted immune responses against anti-TNF therapeutic antibodies. Surprisingly, more than 94% of the antibodies directed against the human(ized) biologicals adalimumab, certolizumab and golimumab are neutralizing.

Even the antibody response to the chimeric infliximab, partly of mouse origin, was still largely neutralizing (for at least 90%). Van Schie: “We wondered whether this restricted response is due to the nature of the anti-TNF binding site, or that the antigen binding site is an inherently immuno-dominant part of the antibody. If so, anti-drug antibodies to any therapeutic antibody might be largely neutralizing”.

Monoclonal antibodies

To shed light on this question van Schie also investigated the antibody response to natalizumab, a humanized IgG4 antibody against α4-integrin. Natalizumab is used to treat multiple sclerosis. About one in 20 patients develops antibodies that diminish efficacy of this drug. Van Schie assessed the polyclonal immune response of 15 of those patients. Furthermore, she cloned three human monoclonal antibodies derived from B cells from two of these patients.

All three monoclonal antibodies were neutralizing: they can block the binding of natalizumab to α4-integrin expressed on Jurkat cells. For all patients tested, at least 91% of all different anti-drug antibodies were neutralizing. “We think that the immune response towards all antibody therapeutics may preferentially be directed to the antigen binding site of the drug”, says van Schie, “And therefore anti-drug antibodies may intrinsically neutralize these therapeutics, if produced in large amounts”.


Therapeutic antibodies are increasingly used to treat various diseases ranging from inflammatory and auto-immune diseases to cancer. They are immunogenic to various degrees, and unwanted anti-drug antibody formation may cause loss of response and occasionally cause hypersensitivity reactions. Even fully human therapeutic antibodies contain at least one part that is foreign to the immune system: the antigen binding site. Therefore all monoclonal therapeutics are to some extent prone to be immunogenic. The results of this study have implications for the development of new therapeutic antibodies and the way immunogenicity will be monitored during drug development and, if necessary, in routine clinical care.


1. van Schie et al. Neutralizing capacity of monoclonal and polyclonal anti-natalizumab antibodies: The immune response to antibody therapeutics preferentially targets the antigen-binding site. J Allergy Clin Immunol 2016 
2. van Schie et al. The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region. Ann Rheum Dis. 2015 Jan; 74(1):311-4


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Last edited on: 3 January 2017