Daratumumab
Daratumumab is directed against CD38 and it has been suggested that it
may be effective in reducing preformed antibodies and desensitizing
patients, given its effect on plasma cell elimination. Only case reports
have been published so far, and there has been concerns whether this
drug could cause depletion also of regulatory B cells and thus induce a
T cell mediated rejection [43]. Currently two clinical trials are in
progress including highly HLA-sensitized patients awaiting kidney
transplantation. From the summaries of study plans (ClinicalTrials.gov
ID NCT05145296 and NCT04204980) it is not clear whether samples to
estimate PK will be collected. Obviously this would be of particular
interest in the situation where one may expect toxicity to be a limiting
factor.
Tocilizumab and Clazakizumab The currently approved indications for tocilizumab are rheumatoid
arthritis and some other autoimmune diseases as well as the treatment of
Covid-19 for selected patients. This drug is acting via inhibition of
the IL-6 receptor. Tocilizumab has shown some promising results both in
the treatment of AMBR and in desensitization, and the potential for such
treatment both in kidney, lung and heart transplantation has been
discussed in several recent papers [30, 44-47]. More rigorous and
sufficiently large trials are needed to clarify the role for tocilizumab
as well as other IL-6 or IL-6R inhibitors in these settings. Meanwhile
there are also studies that indicate large variability in the PK of
tocilizumab. Such data have been collected for tocilizumab when used on
its label indications, however there are also recent studies in
transplant recipients showing the significant variability in PK. A few
of these studies have also used PK models in order to characterize the
parameters in detail and even indicated association between tocilizumab
concentrations and effects like reduction in anti-HLA antibodies [9]
and albuminuria [48] while others did not find such correlations
[49]. It is a challenge to arrange prospective studies that are able
to provide evidence for the benefit of TDM. One opportunity that could
be pursued, is to involve the measurement of drug concentrations as a
sub-protocol in clinical trials that are planned to demonstrate
effectiveness by clinical endpoints.
Clazakizumab is an
IL-6 antagonist which has also been suggested for the treatment of AMBR.
So far only small studies have been reported [30]. However a large
phase 3 multicentre clinical trial is ongoing, and according to the
protocol (IMAGINE-trial: ClinicalTrials.gov identifier: NCT03744910)
samples will be collected during the first three weeks to provide
individual pharmacokinetic parameters. The anticipated study population
of 350 patients should guarantee that these data will be of great
interest for clazakizumab as well as for the discussion of the
personalization of biologicals in general in the post-tx setting.