A novel, combinatory passive immunotherapy for AD treatment in the McGill AD rat model

Presented by Edward WilsonDoctoral Candidate, Integrated Program in Neuroscience,

McGill University

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

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

Evoking the plasmin cascade

Bruno and Cuello, Proc Natl Acad Sci 2006

Directly degrades Aβ

Leon et al, J Alz Disease 2010

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

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

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

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

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

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

Passive immunization

• Promising clinical trials

• No immune response is required

• Treatment can be easily discontinued

• Specific targeting

Thank You

Group members: Rebecca Skerrett, Tatiana Cerneira, Paulina Davis, Sarah Hescham