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Anti-drug antibody generation : How to take advantage of immunogenicity and effectively monitor your therapeutic drug

 

With the increasing use of biologics in therapies, the unwanted immunogenicity of a therapeutic antibody may lead to the in-vivo generation of anti-drug antibodies a.k.a. ADA.

 

ADAs may affect drug efficacy and safety via the formation of drug-ADA immune complexes, intermediates that can have a variety of downstream effects in patients.

 

Nevertheless, in the context of clinical patient monitoring and biosimilar development, the control of the custom generation of anti-drug antibodies proves to be a vital necessity for Biotech and Pharma companies.

 

High specificity and high affinity anti-drug antibodies are ideal for detection and quantification of therapeutic small molecules or antibodies during the drug development process.

 

When the therapeutic is a chemical entity, the generation of the ADA requires breaking the immune tolerance, often playing with analogs and particular coupling strategies of the small molecule of interest, during the immunisation and screening stages.

 

When the therapeutic is an antibody, the generated ADA secondary antibody is an anti-idiotype antibody. The idiotype of an antibody is a particular conformation of the variable part of the immunoglobulin enabling specific recognition of the antigen (1).

 

Anti-drug antibodies research tool can then be used in :

  • pharmacokinetic (PK) studies to determine the free, bound or total drug concentrations in ELISA assays,
  • pharmacodynamics (PD) studies to evaluate the effect of the drug on the body,
  • immunogenicity in-vitro assays as a reference standard.

 

Thanks to effective B cells isolation and screening techniques, you’ll be able to raise monoclonal antibodies for different purposes :

 

  • When the paratope and the idiotope overlap with one another, custom paratope specific anti-idiotype antibodies compete with the target antigen for the same binding site of the antibody drug. The ADA neutralizing, or blocking antibody, is used for free antibody measurement.
  • When the idiotope is localized outside the antigen binding site, custom non-inhibitory anti-idiotype antibodies is used to detect and quantify total therapeutic antibody drug (free and bound).
  • Custom drug-target complex binders are tools that specifically recognize only the antibody-drug antigen complex and are used to quantify bound drug.

 

 

REFERENCE

 

(1) J.Oudin et M.Michel, « Une nouvelle forme d'allotypie des globulines γ du sérum de lapin apparemment liée à la fonction et à la spécificité anticorps », C.R. Acad. Sc.,‎ 1963, 257, p.805-808