title: Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies.
abstract: Immunotherapy is a promising strategy for the treatment of Alzheimer's disease (AD). Antibodies directed against Amyloid Beta (Aβ) are able to successfully clear plaques and reverse cognitive deficits in mouse models. Excitement towards this approach has been tempered by high profile failures in the clinic, one key issue has been the development of inflammatory side effects in the brain (ARIAs). New antibodies are entering the clinic for Alzheimer's disease; therefore, it is important to learn all we can from the current generation. In this study, we directly compared 3 clinical candidates in the same pre-clinical model, with the same effector function, for their ability to clear plaques and induce inflammation in the brain. We produced murine versions of the antibodies: Bapineuzumab (3D6), Crenezumab (mC2) and Gantenerumab (chGantenerumab) with an IgG2a constant region. 18-month transgenic APP mice (Tg2576) were injected bilaterally into the hippocampus with 2 µg of each antibody or control. After 7 days, the mice tissue was analysed for clearance of plaques and neuroinflammation by histology and biochemical analysis. 3D6 was the best binder to plaques and in vitro, whilst mC2 bound the least strongly. This translated into 3D6 effectively clearing plaques and reducing the levels of insoluble Aβ, whilst chGantenerumab and mC2 did not. 3D6 caused a significant increase in the levels of pro-inflammatory cytokines IL-1β and TNFα, and an associated increase in microglial expression of CD11B and CD68. chGantenerumab increased pro-inflammatory cytokines and microglial activation, but minimal changes in CD68, as an indicator of phagocytosis. Injection of mC2 did not cause any significant inflammatory changes. Our results demonstrate that the ability of an antibody to clear plaques and induce inflammation is dependent on the epitope and affinity of the antibody.
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, UK. jpf1g11@soton.ac.uk.
authors.forename: James P
authors.initials: JP
authors.lastname: Fuller
authors.affiliation: Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Stavenhagen
authors.affiliation: Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Christensen
authors.affiliation: Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Kartberg
authors.affiliation: Cancer Sciences, University of Southampton, Southampton, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Teeling
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D007155:Immunologic Factors; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C587672:IL1B protein, mouse; C571128:gantenerumab; C545458:bapineuzumab; C573372:crenezumab
keywords: Alzheimer’s disease; Bapineuzumab; Crenezumab; Gantenerumab; Immunotherapy; Inflammation