LAUSR

With interest we read the review by Levy et al. [1] that provides a thorough overview of current and future therapies aiming to treat vasoplegia, an ubiquitous phenomenon in shock. In their work, the authors dedicated a section to the novel adrenomedullin (ADM)-binding antibody adrecizumab, which is mentioned as an ADM blocking compound in the section title. Recently published studies demonstrate that blocking of ADM does not accurately describe adrecizumab’s mechanism of action, though. In contrast to what is often intuitively assumed, not all antibodies completely inhibit the activity of their targets. The extent of signaling inhibition can vary greatly, depending on the epitope to which the antibodies bind and other factors, such as antibody concentrations. In contrast to C-terminus binding anti-ADM antibodies which completely inhibit ADM signaling, antibodies against the N-terminus of ADM, including the humanized monoclonal antibody adrecizumab, only marginally inhibit ADM activity, despite their high affinity and even when applied in vast molar excess over ADM [2]. Interestingly, animal and human data reveal a strong, dose-dependent increase of plasma ADM concentrations upon adrecizumab infusion [3, 4], which cannot be explained by increased production of ADM. A mechanistic explanation for this occurrence was recently proposed [5]. Excess antibody that remains in the circulation is thought to drain ADM from the interstitium into the circulation, since ADM is small enough to cross the endothelial barrier, whereas the antibody is not. While adrecizumab only partially inhibits ADM signaling, the strong concentration increase of ADM (complexed with