2. Alzheimer’s Disease
2010
Multifactorial dementia More than
35 millions
Memory loss (first short term) people
Apathy
Confusion Risk factors
Language problems
Cardiovascular risk
Dependance upon caregivers
Ageing
Genetic factors
Under-stimulated
environment
Reitz, C. et al. Nat. Rev. Neurol. 7, 137–152 (2011) 2
3. Mechanisms
Misfolded proteins
Oxidative and
inflammatory damage
Energy failure and
synaptic dysfunction
Dementia
3
Henry W. Querfuth, Frank M. LaFerla. Alzheimer’s Disease. New England Journal of Medicine, 2010;362(4):329-344
4. Misfolded proteins :
Focus on Aβ aggregates
APP = Amyloid Precursor Protein
Aβ40
Aβ42 is toxic and
associated with
Alzheimer disease
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) 4
6. The Aβ pathway : trials
Vaccination (AN-1792 = AIP-001)
Phase IIa, NCT00021723 Ongoing
Diminution of plaques
Encephalitis
No cognitive or survival benefit 2 monoclonal antibodies
against Aβ, Phase III :
Bapineuzumab, Solanezumab
Passive immunization (bapineuzumab)
Phase II, NCT00112073 Human Immune Globulin IV,
Phase III
Vasogenic cerebral oedema
γ-secretase inhibitor (LY450139)
6
Henry W. Querfuth, Frank M. LaFerla. Alzheimer’s Disease. New England Journal of Medicine, 2010;362(4):329-344
8. Structure of Antibody
CDR: Complementary Determining Region
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. 8
PNAS Early Edition, October 2011
9. Motif-grafting strategy
N-ter
C-ter
Gammabodies:
Grafted-Amyloid Motif Antibodies
C ter Aβ motif
=> reactive with Aβ soluble oligomers
Central Aβ motif
=> reactive with Aβ fibrils
The grafted motifs target the
corresponding peptide segment
within misfolded Aβ conformers
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. 9
PNAS Early Edition, October 2011
10. Gammabodies: Motif-grafting strategy
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
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. 10
PNAS Early Edition, October 2011
11. Which interactions?
Hypothesis : Homotypic interaction
Aβ motifs Same Aβ motifs
Antibody Conformers
Competitive binding analysis
Gammabodies
VS
Sequence-specific monoclonal antibodies against Aβ
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 11
β. PNAS Early Edition, October 2011
12. Competitive binding analysis
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 12
β. PNAS Early Edition, October 2011
13. Neutralisation of oligomers and fibrils’
toxicity
Cell culture Reduction of MTT
Cell survival
Aβ gammabodies
are nontoxic
Sequences of
grafted Aβ
peptide
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 13
β. PNAS Early Edition, October 2011
14. Neutralisation of oligomers and fibrils’
toxicity
Cell culture
Aβ gammabodies
12-21, 15-24, 18-
27, 30-39 and 33-
42 inhibit the
toxicity of fibrils
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 14
β. PNAS Early Edition, October 2011
15. Neutralisation of oligomers and fibrils’
toxicity
Aβ oligomers are
Cell culture more toxic than Aβ
fibrils
Aβ gammabodies
30-39 and 33-42
inhibit the toxicity
of soluble
oligomers
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 15
β. PNAS Early Edition, October 2011
16. In brief...
Gammabodies
Recognize aggregated Aβ isoforms in a conformation-
specific manner
Via homotypic interactions between amyloidogenic
peptide motifs
Are sequence-specific
Neutralize the toxicity of Aβ oligomers and fibrils
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 16
β. PNAS Early Edition, October 2011
17. Conclusion
Simple design strategy
Hope for Alzheimer Disease
Strategy potentially applicable to other
diseases
Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 17
β. PNAS Early Edition, October 2011
