Article

The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

  • Nature volume 537, pages 5056 (01 September 2016)
  • doi:10.1038/nature19323
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Abstract

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

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Acknowledgements

These studies were funded by Biogen. The authors thank the patients and their family members participating in the aducanumab studies, and the PRIME investigators (Supplementary Information) and staff conducting these studies. Medical writing support, under direction of the authors, was provided by A. Smith at Complete Medical Communications, and was funded by Biogen. We thank N. Pederson, J. Dolnikova and E. Garber for help in generating the recombinant antibodies, D. Fahrer, C. Quigley, M. Themeles, X. Zhang and P. Auluck for help in generating the histological data, and K. Mack for editorial support and coordination of the authors in combining the preclinical and clinical work in this manuscript.

Author information

Author notes

    • Jeff Sevigny
    • , Ping Chiao
    • , Thierry Bussière
    •  & Paul H. Weinreb

    These authors contributed equally to this work.

    • Roger M. Nitsch
    •  & Alfred Sandrock

    These authors jointly supervised this work.

Affiliations

  1. Biogen, Cambridge, Massachusetts 02142, USA

    • Jeff Sevigny
    • , Ping Chiao
    • , Thierry Bussière
    • , Paul H. Weinreb
    • , Leslie Williams
    • , Robert Dunstan
    • , Tianle Chen
    • , Yan Ling
    • , John O’Gorman
    • , Fang Qian
    • , Mahin Arastu
    • , Mingwei Li
    • , Sowmya Chollate
    • , Melanie S. Brennan
    • , Omar Quintero-Monzon
    • , Robert H. Scannevin
    • , H. Moore Arnold
    • , Thomas Engber
    • , Kenneth Rhodes
    • , James Ferrero
    • , Yaming Hang
    • , Alvydas Mikulskis
    •  & Alfred Sandrock
  2. Neurimmune, Schlieren-Zurich 8952, Switzerland

    • Marcel Maier
    • , Jan Grimm
    • , Christoph Hock
    •  & Roger M. Nitsch
  3. Butler Hospital, Providence, Rhode Island 02906, USA

    • Stephen Salloway
  4. Institute for Regenerative Medicine, University of Zurich, Zurich 8952, Switzerland

    • Christoph Hock
    •  & Roger M. Nitsch

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Contributions

T.B., P.H.W., M.M., T.E., K.R., J.G. and R.M.N. designed the preclinical studies, and J.S., Y.L., J.G., J.F., C.H., R.M.N. and A.S. designed the clinical study. P.C. led the imaging implementation for the clinical study. T.C. and J.O. were clinical study statisticians. T.B., P.H.W., M.M., R.D., F.Q., M.A., M.L., S.C., M.S.B., O.Q.-M., R.H.S., H.M.A., T.E., J.G. and R.M.N. generated, analysed, and/or interpreted data from preclinical studies. T.B., P.H.W., M.M., R.D., F.Q., M.A., M.L., S.C., M.S.B., O.Q.-M., R.H.S., H.M.A., T.E., K.R., J.G., C.H., R.M.N. and A.S. critically reviewed preclinical sections of the manuscript. J.S., P.C., L.W., S.S., T.C., Y.L., J.O., J.F., Y.H., A.M., J.G., C.H., R.M.N. and A.S. analysed and interpreted clinical study data and critically reviewed clinical sections of the manuscript. All authors approved the final version of the manuscript for submission. Biogen and Neurimmune reviewed and provided feedback on the paper. The authors had full editorial control of the paper, and provided their final approval of all content.

Competing interests

J.S., P.C., T.B., P.H.W., L.W., R.D., T.C., Y.L., J.O., F.Q., M.A., M.L., S.C., M.S.B., O.Q.-M., R.H.S., H.M.A., T.E., K.R., J.F., Y.H., A.M. and A.S. are current or former employees and/or shareholders of Biogen. J.S. is an employee of F. Hoffmann-La Roche Ltd., Basel, Switzerland; R.D. is an employee of AbbVie Inc., Worcester, Massachusetts, USA; M.A. is an employee of Substantial Living, San Francisco, California, USA; M.L. is an employee of Novartis, Cambridge, Massachusetts, USA; S.C. is an employee of SynteractHCR, Carlsbad, California, USA; O.Q.-M. is an employee of Shire, Lexington, Massachusetts, USA; R.H.S. and K.R. are employees of Yumanity Therapeutics, Cambridge, Massachusetts, USA; T.E. is an employee of Takeda Pharmaceuticals, Cambridge, Massachusetts, USA; J.F. is retired. M.M., J.G., C.H. and R.M.N. are employees and shareholders of Neurimmune. S.S. was a site investigator for the PRIME study and received consultation fees from Biogen, and has received research support from Functional Neuromodulation, Merck, Genentech, Roche, Lilly, and Avid Radiopharmaceuticals, and consultation fees from Merck, Piramal, Lilly, Genentech, and Roche. He owns no stock options or royalties. Biogen has filed and licensed certain patent applications pertaining to Aducanumab.

Corresponding author

Correspondence to Alfred Sandrock.

Reviewer Information Nature thanks L. Lannfelt, R. Thomas and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This includes Supplementary Methods, a Supplementary Discussion and Results, and a list of the PRIME investigators.

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