The authors noted that ontarget hexamerisation might be achievable with hexamerenhanced polyclonal IgG preparations, although this was not examined. IgG, monoclonal antibodies, Stellabody == 1. INTRODUCTION == Monoclonal antibodies (mAbs) are a wellestablished and still rapidly expanding class of therapeutics that have revolutionized the treatment of a range of human diseases including cancer, inflammation, autoimmunity, and infectious diseases. They form the basis of a highly valuable industry and currently over 100 antibodybased therapies are approved for marketing in the USA and/or Europe by the FDA/EMA, with a further 1200 being investigated in clinical trials.1While (S)-Mapracorat many formats of antibody therapeutics are being explored for clinical use, including bispecifics and antibodyfusion proteins, the majority of FDAapproved therapeutic antibodies are formatted as a typical fulllength IgG consisting of two fragment antigenbinding (Fab) arms linked to a fragment crystallisable (Fc) region.2In this format, mAbs can exert their therapeutic effects through multiple mechanisms. These include (S)-Mapracorat direct neutralization of the target antigen via the Fab arms, which can act also as surrogate ligands wherein the two Fab arms induce surface receptor signaling by crosslinking of their target receptor. Importantly, the Fc region is responsible for much of the biological activity of IgG antibodies and can initiate a variety of proor antiinflammatory responses of the innate and adaptive immune systems which, depending on the context, include activation of proinflammatory Fc receptors, antiinflammatory Fc receptors, or the classical pathway of serum complement.3In addition to triggering the abovementioned effector functions, the Fc region is also responsible for other key biological activities of IgG antibodies including halflife4,5,6and certain intracellular actions, such as IgG opsonised target Emcn degradation mediated through TRIM21.7,8 The IgG Fc region comprises of two domains: the CH2 and CH3 domains. The CH2 domain contains the binding sites for complement C1q and the IgG Fc receptors (FcRs/FcRs). FcRs on immune cells are aggregated by complexed IgG, triggering cellular effector responses. Proinflammatory responses of IgGFcR engagement include cytokine release, as well as antibodydependent cellular cytotoxicity (ADCC) or antibodydependent cellular phagocytosis (ADCP) of IgGopsonised targets. Alternatively, the Fc can also modulate responses by coengagement of a specialized inhibitory FcR (FcRIIb) with ITAMbased signaling receptors. These include the B cell antigen receptor (BCR) resulting in the modulation of B cell activation or proinflammatory activatingtype FcRs thereby modulating IgG immune complex activation of myeloid cells (reviewed elsewhere9). C1q is the hexameric, antibodybinding component of the C1 complex of the complement system. It is comprised of 18 polypeptide chains forming six heterotrimeric collagenhelices that each end in a globular head. The collagenous stalk associates with the protease components of C1; C1r, and C1s. Each globular head can bind to an IgG Fc at the CH2 domain of IgG, each contributing to the avid binding of complexed or (S)-Mapracorat aggregated IgG. This activates C1 and thereby initiates the classical complement cascade, resulting ultimately in the formation of the membrane assault complex (Mac pc), which is the poreforming lytic machinery of the cascade. The consequential lysis of opsonised focuses on is known as complementdependent cytotoxicity (CDC) and is tightly regulated to limit sponsor damage.10 Importantly, the ability to elicit the main IgGdependent effector functions, involving FcR and complement, varies between different IgG subclasses. IgG1 and IgG3 are generally regarded as the most potent, while IgG2 and IgG4 are considered the least potent causes of these immune effector reactions. IgG2 potency has been considered as restricted to the activation of only the His131 allelic form of FcRIIa, even though activation of additional FcRs in situations of high opsonisation and high avidity relationships has been (S)-Mapracorat indicated.11Since IgG4 binds avidly to the inhibitory FcRIIb, it likely plays a role in modulating the (S)-Mapracorat proinflammatory responses of the activatingtype FcR of.