A COMPUTATIONAL METHOD TO PREDICT DISEASE-SPECIFIC EPITOPES IN Aβ, AND ITS APPLICATION TO OLIGOMER-SELECTIVE ANTIBODIES FOR ALZHEIMER’S IMMUNOTHERAPY

Abstract

Treatment for Alzheimer’s disease (AD) has faced the difficult challenge of effectively targeting and clearing toxic and/or propagative species of protein, which together lead to pathology and neurodegeneration. Current evidence points to a cascade of aberrant proteostasis, generally involving cytotoxic tau pathology that is induced by misfolded Aβ oligomer [1,2,3]. A method for identifying antibodies to Aβ that are conformationally-selective to the toxic oligomer, and which also have relatively low affinity to either Aβ monomer or fibril, is thus a highly desired goal that holds significant promise for AD therapy [4]. We employ computational simulations, using molecular dynamics with standardized force-fields. An experimentally-validated structural model of a protofibrillar aggregate is globally biased away from its “native” conformation to be partially unfolded, using molecular dynamics with collective coordinates to yield a set of regions of contiguous primary sequence that are prone to be disordered upon an external challenge in an anomalous cellular environment. We hypothesize these weakly-stable regions are likely to be exposed in nascent protofibrils or oligomers, and that in this context they are present in an alternate conformation than they are either in the free monomer ensemble or in the context of the fibril. They thus constitute oligomer-specific epitope predictions. Oligomer-specific epitope predictions will be presented for Aβ. Cyclic peptides of these epitope primary sequences are both computationally and experimentally generated, which constitute antigenic targets. Clustering analysis, curvature, exposure to solvent, solubility, dihedral angle distribution, and Ramachandran angle distributions are all used to characterize the conformational properties of predicted epitopes, which quantify the distinction between the antigenic profile when presented in the context of the oligomer from that in either the monomer or fibril. A set of five oligomer-specific epitopes are proposed for Aβ. The computational epitope discovery approach has the potential to produce multiple Aβ oligomer-specific antibodies. Acknowledgements: ProMIS Neurosciences, the Canadian Institutes of Health Research and the Alberta Prion Research Institute. [1] Hadley, KC et al. eLife(2015). [2] Ittner LM, Gotz J, Nat Rev Neurosci (2011). [3] Vasconcelos B et al. Acta Neuropathol (2016). [4] Sevigny J, et al. Alzheimers Dement (2015).