Binding Promiscuity of Therapeutic Factor VIII.

The binding promiscuity of proteins defines their ability to indiscriminately bind multiple unrelated molecules. Binding promiscuity is implicated, at least in part, in the off-target reactivity, nonspecific biodistribution, immunogenicity, and/or short half-life of potentially efficacious protein drugs, thus affecting their clinical use. In this review, we discuss the current evidence for the binding promiscuity of factor VIII (FVIII), a protein used for the treatment of hemophilia A, which displays poor pharmacokinetics, and elevated immunogenicity. We summarize the different canonical and noncanonical interactions that FVIII may establish in the circulation and that could be responsible for its therapeutic liabilities. We also provide information suggesting that the FVIII light chain, and especially its C1 and C2 domains, could play an important role in the binding promiscuity. We believe that the knowledge accumulated over years of FVIII usage could be exploited for the development of strategies to predict protein binding promiscuity and therefore anticipate drug efficacy and toxicity. This would open a mutational space to reduce the binding promiscuity of emerging protein drugs while conserving their therapeutic potency.

Temperature sensitivity of bat antibodies links metabolic state of bats with antigen-recognition diversity.

The bat immune system features multiple unique properties such as dampened inflammatory responses and increased tissue protection, explaining their long lifespan and tolerance to viral infections. Here, we demonstrated that body temperature fluctuations corresponding to different physiological states in bats exert a large impact on their antibody repertoires. At elevated temperatures typical for flight, IgG from the bat species Myotis myotis and Nyctalus noctula show elevated antigen binding strength and diversity, recognizing both pathogen-derived antigens and autoantigens. The opposite is observed at temperatures reflecting inactive physiological states. IgG antibodies of human and other mammals, or antibodies of birds do not appear to behave in a similar way. Importantly, diversification of bat antibody specificities results in preferential recognition of damaged endothelial and epithelial cells, indicating an anti-inflammatory function. The temperature-sensitivity of bat antibodies is mediated by the variable regions of immunoglobulin molecules. Additionally, we uncover specific molecular features of bat IgG, such as low thermodynamic stability and implication of hydrophobic interactions in antigen binding as well as high prevalence of polyreactivity. Overall, our results extend the understanding of bat tolerance to disease and inflammation and highlight the link between metabolism and immunity.