An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ.
Passive immunization against β-amyloid (Aβ) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimer's disease (AD). However, traditional passive immunization approaches carry the risk of Fcγ receptor-mediated overactivation of microglial cells, which may contribute to an inappropriate proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. Here, we describe the generation of a humanized anti-Aβ monoclonal antibody of an IgG4 isotype, known as MABT5102A (MABT). An IgG4 subclass was selected to reduce the risk of Fcγ receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of Aβ, protected against Aβ1-42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic Aβ oligomers by microglia. Furthermore, MABT-mediated amyloid plaque removal was demonstrated using in vivo live imaging in hAPP((V717I))/PS1 transgenic mice. When compared with a human IgG1 wild-type subclass, containing the same antigen-binding variable domains and with equal binding to Aβ, MABT showed reduced activation of stress-activated p38MAPK (p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNFα. We propose that a humanized IgG4 anti-Aβ antibody that takes advantage of a unique Aβ binding profile, while also possessing reduced effector function, may provide a safer therapeutic alternative for passive immunotherapy for AD. Data from a phase I clinical trial testing MABT is consistent with this hypothesis, showing no signs of vasogenic edema, even in ApoE4 carriers.
AC Immune SA, 1015 Lausanne, Switzerland.
Oskar
O
Adolfsson
Maria
M
Pihlgren
Nicolas
N
Toni
Yvan
Y
Varisco
Anna Lucia
AL
Buccarello
Katia
K
Antoniello
Sophie
S
Lohmann
Kasia
K
Piorkowska
Valerie
V
Gafner
Jasvinder K
JK
Atwal
Janice
J
Maloney
Mark
M
Chen
Alvin
A
Gogineni
Robby M
RM
Weimer
Deborah L
DL
Mortensen
Michel
M
Friesenhahn
Carole
C
Ho
Robert
R
Paul
Andrea
A
Pfeifer
Andreas
A
Muhs
Ryan J
RJ
Watts
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D018613:Microscopy, Confocal; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019707:Receptors, Chemokine / Q000235:genetics; D018709:Statistics, Nonparametric; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D007074:Immunoglobulin G; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins; D048051:p38 Mitogen-Activated Protein Kinases