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AC IMMUNE SA filed this Form 20-F on 03/21/2019
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Figure 12: The Abeta salt-bridge hairpin



Based on Ultsch, et. al., Sic Rep 2016


The illustration above is of the Abeta mid-domain highlighting the salt-bridge interaction between Asp23 and Lys28 in red. This interaction is present in Abeta oligomers and aggregates. Crenezumab epitope residues important for binding are indicated in green.


Supportive high resolution imaging data, from APP/PS1 mice dosed with crenezumab, demonstrated that crenezumab localizes to brain areas with putative high concentrations of Abeta oligomers (i.e. the periphery of amyloid plaques and hippocampal mossy fibers) and that crenezumab does not bind to the dense core of plaques or vascular amyloid in these AD transgenic mice. (Atal et al, Clinical Trials on Alzheimer’s Disease (CTAD) 2017)


Characteristics and benefits of crenezumab’s effector function


Crenezumab is a humanized IgG4 antibody selected as a clinical candidate for its unique binding and safety properties. As crenezumab binds multiple forms of Abeta (i.e., monomers, oligomers, fibrils and plaques), and will be present post-dose in the brain and periphery as an antibody/target complex, the safety of downstream events triggered by these immune complexes becomes a crucial consideration. Thus, the human IgG4 backbone was selected as a safer alternative to a human IgG1 for this immuno-therapy. The crenezumab IgG4 backbone confers reduced activation of Fc gamma receptors (FcγRs) in comparison to IgG1 (unpublished data), and was shown to minimize FcγR-mediated inflammatory activation of microglia (Adolfsson et al., 2012). Inflammatory activation in the CNS was shown to contribute to neurotoxicity (see review by Heneka, et. al. 2015., Ardura-Fabregat, et. al., CNS Drugs 2017, Kinney, et. al., Alz Demen 2018). Even if IgG4 FcγR-mediated inflammatory events are reduced compared to IgG1, microglial and macrophage phagocytosis is maintained. This is a very important safety factor reflected in the comparison with AD clinical trials involving antibodies using an IgG1 backbone to target aggregated Abeta.


Strategies invoking the formation of anti-Abeta IgG1 immune complexes (i.e., which maintain fully active FcγR-mediated effector functions) have reported dose-related adverse events, such as amyloid-related imaging abnormalities, suggestive of vasogenic edema or effusions (ARIA-E) and microhemorrhage (ARIA-H; Fuller et al., 2014). Crenezumab was designed as an IgG4 based on the hypothesis that an antibody with reduced effector function would have a lower risk of inducing vasogenic edema, and to provide a safety advantage over anti-Abeta antibodies with a full effector IgG1 backbone. Selecting IgG4 as the backbone allows the antibody-Abeta complex to interact with microglia Fc receptors with lower affinity, as was observed when comparing the binding of the different backbone variants to FcγRIa, FcγRIIaH131, FcγRIIaR131, FcγRIIb, FcγRIIIaF158, and FcγRIIIaV158. This translated into an optimal balance to allow efficient antibody-mediated Abeta phagocytosis (Adolfsson et. al., 2012).



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