Development of Monoclonal Antibody Therapeutics for Alzheimer's Disease

10.4103/TPSY.TPSY_31_22

Masatoshi Takeda

aducanumab ； immunotherapy ； lecanemab ； memory impairment

台灣精神醫學

36卷4期（2022 / 12 / 01）

148 - 156

英文

Background: In a previous review article in the Taiwanese Journal of Psychiatry (Takeda and Tagami: Taiwanese J. Psychiatry 2020; 34: 152-61), we gave the development status of drugs for Alzheimer's disease, presented a relatively pessimistic view, and highlighted the difficulties in their development. Methods: Since I have witnessed some encouraging development of monoclonal antibody therapeutics against Alzheimer's disease, I have decided to contribute this article. I reviewed new data from published journals and from internal reports of pharmaceutical companies. I have also offered some explanations and comments. Results: In 2021, I saw promising clinical trial results reporting the use of aducanumab, a monoclonal antibody treatment against amyloid β protein, and the U.S. Food and Drug Administration (FDA) announced a decision for expedited approval of aducanumab. But the results of aducanumab's phase III clinical trials were considered by some to be insufficient for the approval, and the FDA's decision was controversial. The European and Japanese regulatory authorities did not approve aducanumab. In September 2022, however, more promising results were announced from Phase III clinical trials of another monoclonal antibody, lecanemab. Conclusion: In this review, I have recounted the state of the arts of drugs for treating dementia and highlighted remarkable recent progress in the development of monoclonal antibody therapeutics for Alzheimer's disease.

1. Takeda, M,Ashizuka, A(2021).Development of monoclonal antibody therapy against Alzheimer’s disease.Cogntion and Rehabilitation,2,50-59.
   連結：
2. Takeda, M,Tagami, S(2020).A history of antidementic drug development in Japan.Taiwan J Psychiatry,34,152-161.
   連結：
3. 2020 Alzheimer’s disease facts and figures.Alzheimer’s Dement,16,391-460.
4. Arndt, JW,Qian, F,Smith, BA(2018).Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β.Sci Rep,8,6412.
5. Borchelt, DR,Thinakaran, G,Eckman, CB(1996).Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.Neuron,17,1005-1013.
6. Citron, M(2010).Alzheimer’s disease: Strategies for disease modification.Nat Rev Drug Discov,9,387-398.
7. Hardy, J,Selkoe, DJ(2002).The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics.Science,297,353-356.
8. Janus, C,Pearson, J,McLaurin, J(2000).A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease.Nature,408,979-982.
9. Kaplon, H,Chenoweth, A,Crescioli, S,Reichert, JM(2022).Antibodies to watch in 2021.mAbs,13,1860476.
10. Kaplon, H,Muralidharan, M,Schneider, Z,Reichert, JM(2020).Antibodies to watch in 2020.mAbs,12,1703531.
11. Knopman, DS,Jones, DT,Greicius, MD(2021).Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019.Alzheimers Dement,17,696-701.
12. Logovinsky, V,Satlin, A(2016).Safety and tolerability of BAN2401-A clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody.Alzheimers Res Ther,8,14.
13. Monsonego, A,Weiner, HL(2003).Immunotherapeutic approaches to Alzheimer’s disease.Science,302,834-838.
14. Morgan, D,Diamond, DM,Gottschall, PE(2000).A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease.Nature,408,982-985.
15. Nakanishi, M,Nakashima, T(2014).Features of the Japanese national dementia strategy in comparison with international dementia policies: How should a national dementia policy interact with the public health- and social-care systems?.Alzheimers Dement,10,468-476.e3.
16. Nicoll, JA,Wilkinson, D,Holmes, C(2003).Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report.Nat Med,9,448-452.
17. Schenk, D,Barbour, R,Dunn, W(1999).Immunization with amyloidbeta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.Nature,400,173-177.
18. Söllvander, S,Nikitidou, E,Gallasch, L(2018).The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death.J Neuroinflammation,15,98.
19. Takeda, M(2020).Japanese policy against dementia.Igaku Ayumi,272,545-546.
20. Tucker, S,Möller, C,Tegerstedt, K(2015).The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice.J Alzheimers Dis,43,575-588.
21. Wisniewski, T,Konietzko, U(2008).Amyloid-beta immunisation for Alzheimer’s disease.Lancet Neurol,7,805-811.