antibody for alzheimer disease
TRANSCRIPT
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Antibody may help fight Alzheimer’s
Claire JagodzinskiPauline FlipoJanuary 2012
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Multifactorial dementia
Memory loss (first short term)
Confusion
Apathy
Language problems
Dependance upon caregivers
2010More than 35 millions
people
Cardiovascular risk
Genetic factors
Ageing
Risk factors
Under-stimulated environment
Reitz, C. et al. Nat. Rev. Neurol. 7, 137–152 (2011)
Alzheimer’s Disease
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Mechanisms
Henry W. Querfuth, Frank M. LaFerla. Alzheimer’s Disease. New England Journal of Medicine, 2010;362(4):329-344
Misfolded proteins
Oxidative and inflammatory damage
Energy failure and synaptic dysfunction
Dementia
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Misfolded proteins : Focus on Aβ aggregates
APP = Amyloid Precursor Protein
β secretase(BACE-1)
γ secretase
Secretases lead to a pathological processing of APP
Reitz, C. et al. Nat. Rev. Neurol. 7, 137–152 (2011)
Aβ42 is toxic and associated with
Alzheimer disease
Aβ40
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Correlation
Neurotoxicity Aβ Oligomers and fibrils
Transient and hazardous
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The Aβ pathway : trials
Henry W. Querfuth, Frank M. LaFerla. Alzheimer’s Disease. New England Journal of Medicine, 2010;362(4):329-344
Vaccination (AN-1792 = AIP-001)
Phase IIa, NCT00021723
Diminution of plaquesEncephalitis
No cognitive or survival benefit
Passive immunization (bapineuzumab)
Phase II, NCT00112073
Vasogenic cerebral oedema
Ongoing
2 monoclonal antibodies against Aβ, Phase III :
Bapineuzumab, Solanezumab
Human Immune Globulin IV, Phase III
γ-secretase inhibitor (LY450139)
7http://www.fiercebiotech.com/press-releases/researchers-design-alzheimers-antibodies
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Structure of Antibody
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
CDR: Complementary Determining Region
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C-terN-ter
Motif-grafting strategy
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
Gammabodies: Grafted-Amyloid Motif Antibodies
Central Aβ motif => reactive with Aβ fibrils
C ter Aβ motif => reactive with Aβ soluble oligomers
The grafted motifs target the corresponding peptide segment within misfolded Aβ conformers
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Gammabodies: Motif-grafting strategy
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
Sequence-specific antibodies: Detection of each Aβ conformer
6E10: N-ter (Aβ 1-16)
4G8: middle region (Aβ 18-22)
9F1: C-ter (Aβ 34-39)
Conformation-specific antibodies:Specifically recognize folded conformers of amyloidogenic
proteins
OC, WO1: fibrils
A11: oligomers
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Which interactions?
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
Hypothesis : Homotypic interaction
Aβ motifsAntibody
Same Aβ motifsConformers
Competitive binding analysis
Gammabodies
Sequence-specific monoclonal antibodies against Aβ
VS
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Competitive binding analysis
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
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Neutralisation of oligomers and fibrils’ toxicity
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
Cell culture
Aβ gammabodies are nontoxic
Reduction of MTTÞ Cell survival
Sequences of grafted Aβ
peptide
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Neutralisation of oligomers and fibrils’ toxicity
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
Cell culture
Aβ gammabodies 12-21, 15-24, 18-27, 30-39 and 33-
42 inhibit the toxicity of fibrils
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Neutralisation of oligomers and fibrils’ toxicity
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
Cell culture
Aβ gammabodies 30-39 and 33-42
inhibit the toxicity of soluble oligomers
Aβ oligomers are more toxic than Aβ
fibrils
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In brief...
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
Gammabodies
Recognize aggregated Aβ isoforms in a conformation-specific manner
Neutralize the toxicity of Aβ oligomers and fibrils
Via homotypic interactions between amyloidogenic peptide motifs
Are sequence-specific
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Conclusion
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011
Simple design strategy
Hope for Alzheimer Disease
Strategy potentially applicable to other diseases