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It is almost a given that when a foreign biologically active molecule is injected into humans it will incite immune reactions leading to antibody formation against the molecule, which at high levels of titer and affinity can interfere with its pharmacokinetic properties and block the molecule from binding to its receptor, rendering it biologically inert. Though the degree of foreign-ness tends to be the strongest driving force for the production of antibodies, the mode of administration (sc, IM, IV), dose, and frequency may also impact their development. The development of monoclonal antibody (MAb) technology has allowed for the production of very specific target-directed immunotherapies that have revolutionized the treatment of autoimmune diseases in particular, such as rheumatoid arthritis, systemic lupus erythematosus, and even multiple sclerosis (MS). Though technology has also made it possible to “humanize” the MAb as much as possible, by nature the MAb must be at least a little foreign, since the specific part of the antibody that binds to the human receptor (referred to as the idiotype) is most likely generated in a different species (figure).
Assessing what impact anti-drug neutralizing antibodies (NAbs) have on drug efficacy requires attention to two different categories of drug effect: that on drug measures, such as pharmacokinetics and bioactivity, and the effect on specific disease outcome measures. Drug measures in some cases can be readily quantitated (e.g., natalizumab levels) or inferred from bioactivity measures (e.g., MxA protein expression in response to interferon-β) (IFNβ). Presuming that during the development of these agents, both the sustainable levels and their subsequent bioactivity have been optimized, neurologists assume that once administered, agents are fully capable of maximizing their effects on disease measures, which can be assessed in clinical trials. However, anti-drug antibodies can profoundly affect these measures, …
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