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pegol, a humanized injectable anti-TNF, is a pegylated Fab’ fragment and has dem-
onstrated efficacy in inducing and maintaining remission in CD [ 10 , 11 ].
In addition to the anti-TNFs, a new class of biologics inhibiting leukocyte traf-
ficking has also been approved for the management of IBD. Natalizumab, a mono-
clonal antibody directed against the alpha-4 integrin, was the first of these agents
and is FDA approved for both CD and multiple sclerosis [ 12 ]. Widespread utiliza-
tion of natalizumab in CD has been limited largely due to its known association with
progressive multifocal leukoencephalopathy (PML) [ 13 ]. Vedolizumab, a biologic
therapy targeting the alpha-4 beta-7 heterodimer, lending this compound gut-
specific inhibition of leukocyte trafficking, is approved for both CD and UC and has
not been associated with an increased risk of PML [ 14 ].
The Clinical Impact of Immunogenicity and Pharmacokinetics
of Biologic Therapies in IBD
While both anti-TNFs and anti-integrins have demonstrated clear benefit in inducing
and maintaining remission in CD and UC, it was recognized early on that these
compounds were potentially immunogenic, likely secondary to their large amino
acid-based structure [ 15 ]. In the ACCENT I trial, one of the first clinical trials of
maintenance infliximab in CD, 28% of individuals had detectable antibodies to the
drug if they had received only one dose of the drug; only 9% of those maintained on
5 mg/kg of the drug had developed antibodies at week 54 [ 4 ]. While the fully human
structure of adalimumab was designed in part to reduce such immunogenicity, phase
3 trials of this agent also demonstrated immunogenicity, with 2.6% of individuals in
the CLASSIC II maintenance trial in CD and 2.9% in the ULTRA maintenance trials
in UC developing antibodies to the drug [ 16 , 17 ]. Antibodies against certolizumab
pegol were appreciated in up to 17.7% of individuals in clinical trials as well [ 11 ,
18 ]. The binding sites, or epitopes, of these anti-drug antibodies can be highly vari-
able, either interfering directly with TNF-α binding or, alternatively, binding to other
epitopes on the drug, thereby hastening their metabolism [ 19 ]. Interestingly, in a
study assessing antibodies to infliximab (ATIs) and their binding sites by Ben- Horin
and colleagues, antibodies directed against the Fab’ fragment of the drug were more
common, while global antibody concentrations were more closely correlated with
an impact on clinical loss of response to the drug [ 19 ]. Similar antibody formation
rates have been appreciated with newer anti-integrin monoclonal antibodies, e.g.,
3.7% of individuals receiving vedolizumab in clinical trials in UC had detectable
antibodies to the drug at some point during the 1-year follow-up period [ 20 ].
With the growing recognition of biologic immunogenicity, researchers also
began to assess the clinical impact of anti-drug antibodies. It has long been recog-
nized that a large percentage of individuals who initially respond to biologic thera-
pies eventually lose this response, with antibody formation being one of the
hypothesized mechanisms. In two early clinical trials of infliximab given episodi-
cally, or on a nonscheduled basis only as needed, the duration of response was
F.I. Scott and M.T. Osterman