Edward Wilson presentation made at the Alzheimer Research Forum webinar held November 7, 2012 (www.alzforum.org)

1. A novel, combinatory passive
immunotherapy for AD treatment in
the McGill AD rat model
Presented by Edward Wilson
Doctoral Candidate, Integrated Program in Neuroscience,
McGill University

2. Immunotherapy trials in humans
• Bapineuzumab Phase III (Janssen/Pfizer) i.v. discontinued
• Solanezumab Phase III (Eli Lilly)
• MABT5102A Phase II (Genentech/AC Immune)
• Gantenerumab Phase II (Hoffmann-LaRoche)
• GSK933776 Phase II (GSK) discontinued
• Ponezumab Phase II (Pfizer/Rhinat) discontinued
• BAN2401 Phase I (Esai/BioArtic)
• Gammagard 10% IGIV Phase III (Baxter HC)
• Octagam 10% IVIG Phase II (OctaPharma) completed
• NewGam 10% IVIG Phase II (Sutter Health)
Adapted from Cindy Lemere

3. Solanezumab
• humanized monoclonal antibody
• binds to the central region of β-amyloid and helps to
remove it before plaque formation
• i.v. treatment for mild-to-moderate AD patients
• Acute treatment of tg mice attenuated or reversed
memory deficits
 No cognitive improvement in patients with fully
established disease

4. Evoking the plasmin cascade
Bruno and Cuello,
Proc Natl Acad Sci 2006
Directly
degrades Aβ

5. Leon et al,
J Alz Disease 2010

6. Aim 1: Does an antibody to
neuroserpin produce beneficial effects
in an AD rat model?
• Hypothesis: Decreasing neuroserpin levels in
the aged McGill rat AD model will lead to
increases in 1) NGF, 2) decreased amyloid
pathology, and 3) improved memory
performance

7. Aim 1: Does an antibody to neuroserpin
produce beneficial effects in an AD rat
model?
• Experimental strategies:
– Passive immunization of 13 month old McGill rats with anti-
neuroserpin antibody at high, low, and intermediate doses by IP
injection every week
– Behavior – Morris Water Maze, novel object recognition and object
location task
– Protein analysis (Western blot) – levels of tPA, plasmin, pro-NGF, NGF,
BDNF, synaptic proteins
– Histology – synaptic density, amyloid pathology
– ELISA analysis – soluble and insoluble Aβ species
– Zymography – activity of tPA and plasmin
• Expectations:
– Increased activation of plasmin will increase Aβ clearance
– Increased NGF and decreased pro-NGF will increase synaptic boutons
of cholinergic neurons
– Increased cognitive performance

8. Aim 2: Does a tandem treatment with
neuroserpin and Aβ-specific antibodies
have synergistic effects?
• Hypothesis: Decreasing neuroserpin levels in
aged McGill rats in conjunction with
stimulating clearance of Aβ will have a greater
effect on 1) amyloid pathology and 2)
cognitive performance than modulating
neuroserpin alone

9. Aim 2: Does a tandem treatment with
neuroserpin and Aβ-specific antibodies
have synergistic effects?
• Experimental strategies:
– Passive immunization of 13 month old McGill rats with Solanezumab and
neuroserpin antibody at low, intermediate, and high doses at 13 months of age
by IP injection every week
– Behavior – Morris Water Maze, novel object recognition and object location
task
– Protein analysis (Western blot) – levels of tPA, plasmin, pro-NGF, NGF, BDNF,
synaptic proteins
– Histology – synaptic density, amyloid pathology
– ELISA analysis – soluble and insoluble Aβ species
– Zymography – activity of tPA and plasmin
• Expectations:
– Aβ clearance will be more efficient than with the neuroserpin antibody alone
– Increased NGF and decreased pro-NGF will increase synaptic boutons of
cholinergic neurons
– Cognitive performance will be improved over Aim 1 due to increased NGF and
increased removal of Aβ

10. Aim 3: Is a tandem treatment with
neuroserpin and Aβ-specific antibodies
able to prevent AD pathology?
• Hypothesis: Treating adult McGill rats with
anti-neuroserpin and anti-Aβ before plaque
deposition stage will 1) prevent the
development of amyloid pathology and 2)
improve early behavioral deficits

11. Aim 3: Is a tandem treatment with
neuroserpin and Aβ-specific antibodies
able to prevent AD pathology?
• Experimental strategies:
– Passive immunization of McGill rats with Solanezumab and neuroserpin
antibody beginning at 3 months of age by IP injection every week
– Analyze at 6 months of age
– Behavior – Morris Water Maze, novel object recognition and object location
task
– Protein analysis (Western blot) – levels of tPA, plasmin, pro-NGF, NGF, BDNF,
synaptic proteins
– Histology – synaptic density, amyloid pathology
– ELISA analysis – soluble and insoluble Aβ species
– Zymography – activity of tPA and plasmin
• Expectations:
– Early clearance of Aβ will prevent amyloid pathology
– Increased NGF and decreased pro-NGF will increase synaptic boutons of
cholinergic neurons
– Early cognitive defects will be reversed

12. Passive immunization
• Promising clinical trials
• No immune response is required
• Treatment can be easily discontinued
• Specific targeting

13. Thank You
Group members: Rebecca Skerrett, Tatiana Cerneira, Paulina Davis, Sarah Hescham