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.