To maximize effectiveness and minimize adverse reactions, an ideal C1INH preparation should exert its inhibitory function preferably or exclusively in ischemic and/or reperfused myocardial tissue similar to the concept of targeting cancer cells by mAbs. In contrast to cancer, the speed of inactivation is also crucial in I/R injury, as for example MBL-MASP-1/-2 complexes clustered together on ischemic endothelial or myocardial cells may escape inactivation by C1INH long enough to activate downstream effector molecules.
Whereas the protein structure is identical, the glycosylation pattern of Conestat alfa at the amino-terminal domain is markedly different from pdC1INH preparations (32). In particular, exposed mannose residues are significantly more prevalent in Conestat alfa compared with pdC1INH (15 vs. <1%), which may influence the binding preference toward lectins and in particular to MBL. Indeed, Gesuete et al. demonstrated high-affinity binding of Conestat alfa to MBL but not of pdC1INH (31). Although this may not directly influence the degree of inhibition by its serpin domain, it may potentially impact on the speed and location of inhibition in the human body. By binding to MBL, Conestat alfa may be hijacked to the primary site of inflammation, where it may immediately inhibit its target proteases before they are able to activate downstream effector molecules. By contrast, pdC1INH is certainly able to limit random complement activation in plasma but may allow considerable escape of inactivation of complement complexes at the tissue level. Interestingly, Conestat alfa remained confined on the ischemic endothelial wall in co-localization to MBL, whereas pdC1INH was also found in the area around the ischemic vessels (31).
However, due to the lack of comparative studies of pdC1INH vs. Conestat alfa in myocardial I/R injury it is premature to draw any definitive conclusions about any difference in efficacy of the two preparations in the setting of AMI.