ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors)  K.L. Winthrop, X. Mariette, J.T. Silva, E. Benamu, L.H. Calabrese, A. Dumusc, J.S. Smolen, J.M. Aguado, M. Fernández-Ruiz  Clinical Microbiology and Infection  Volume 24, Pages S21-S40 (June 2018) DOI: 10.1016/j.cmi.2018.02.002 Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases Terms and Conditions

Fig. 1 Structure of different interleukin-1 (IL-1) -targeted agents. Canakinumab is a fully human IgG1 monoclonal antibody and gevokizumab is a humanized monoclonal antibody, both targeting IL-1β. Anakinra is a recombinant IL-1 receptor antagonist that inhibits the binding of IL-1α and IL-1β to IL-1R by mirroring the mode of action of the endogenous form (IL-1-RA). Rilonacept is a fusion protein composed of the ligand-binding domains of IL-1R1 and IL-1RAcP linked to the Fc portion of human IgG1. Clinical Microbiology and Infection 2018 24, S21-S40DOI: (10.1016/j.cmi.2018.02.002) Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases Terms and Conditions

Fig. 2  Different signalling pathways for interleukin-6 (IL-6) and mode of action of IL-6- or IL-6R-targeted agents. The classic or cis-signalling pathway (a) is restricted to cells that constitutively express the membrane-bound form of IL-6R (mIL-6R), mainly haematopoietic cells, and is supposed to primarily exert housekeeping and physiological functions. Upon binding of IL-6 to mIL-6R, homodimerization of gp130 is induced and a functional receptor complex (IL-6/mIL-6R/gp130) is formed, triggering the downstream signalling cascade. In contrast, the trans-signalling pathway (b) initiates with the binding of IL-6 to the soluble form of IL-6R (sIL-6R), produced by cleavage of mIL-6R and lacking the intracytoplasmic portion. The resulting complex (IL-6/sIL-6R) is able to activate virtually all nucleated cells, because gp130 is expressed ubiquitously in the body. This pathway has been implicated in stress signalling. Tocilizumab is a humanized IgG1 monoclonal antibody targeting both mIL-6R and mIL-6R, whereas siltuximab is a chimeric IgG1 monoclonal antibody that binds to IL-6. Clinical Microbiology and Infection 2018 24, S21-S40DOI: (10.1016/j.cmi.2018.02.002) Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases Terms and Conditions