- Email: [email protected]
Immunotherapy targeting abnormal protein conformation
Oral O2-05: Therapeutics and Therapeutic Strategies: Immunotherapy Methods: In our new approach using molecular biology and immunology methodology, we have engineered and tested modified DepVac containing Multiple Th epitopes (MDepVac) that are expected to activate memory Th cells, which will then provide Th stimulation of B cells specific for the Ab1-11 B cell epitope. Results: Proof of concept was demonstrated in mice immunized with Th epitopes (TT, Flu or HBV) and after generation of memory T cells boosted with MDepVac. We demonstrated the feasibility of pre-existing memory CD4þTh cells to induce rapid and robust antiAb antibody response. At present, we are testing the ability of mice, previously vaccinated with conventional vaccines, which are currently employed for human vaccination, promote more rapid and potent anti-Ab antibody production when boosted once with MDepVac in contrary to non-vaccinated animals. Conclusions: These experiments simulate the situation in people repeatedly vaccinated/infected with different pathogens. This approach will be beneficial for people with early stage AD and elderly with immunosenescence.
O2-05-03
IMMUNOTHERAPY TARGETING ABNORMAL PROTEIN CONFORMATION
Thomas Wisniewski1, Frances Prelli1, Henrieta Scholtzova1, Erika Chung1, Pankaj D. Mehta2, Regina Kascsak2, Richard Kascsak2, Fernando Goni1, 1 NYU School of Medicine, New York, NY, USA; 2New York Staten Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease is the most common of the conformational neurodegenerative disorders, where the pathogenesis is linked to a normal protein undergoing a shape change into a pathological conformer with a high b-sheet content. In the case of AD this involves both amyloid b and abnormally phosphorylated tau forming toxic oligomeric structures. In the case of another conformational disorder, the prion diseases, the pathogenesis is linked to a change in the cellular prion protein (PrPC) into the disease associated PrPSc. Currently there is no effective therapy for any of these disorders. However, immunomodulation holds great promise. Major problems with this approach include: the potential of toxicity from neuroinflamation related to excessive cell mediated autoimmunity and the immunological targeting of both the normal and abnormal Ab peptide. In addition, tau related pathology has not been addressed. Methods: We have developed a novel immunotherapeutic approach that may potentially overcome many of these weaknesses. We used active immunization with aggregated British amyloid (ABri) related peptides. This rare form of familial human amyloidosis is associated with a mis-sense mutation in a stop codon resulting in the production of a highly amyloidogenic protein with no sequence homology to other native human proteins. Results: Our preliminary data indicates that mice immunized with aggregated/oligomerized preparations of ABri recognized heterologous amyloid structures including oligomeric Ab and PrPSc. Monoclonal antibodies were derived from successfully vaccinated animals and interestingly some of them recognize oligomeric Aß but not monomeric Ab, as well as paired helical filaments and PrPSc. ABri has no sequence homology with Ab, tau or PrP; hence, this immune response is not amino acid sequence specific but represents a preferential targeting of the pathological protein/peptide conformations shared by Ab, tau and PrPSc. We also show that active immunization of APP/PS1 AD Tg mice with ABri produces significant cognitive benefits. Conclusions: Our results suggest that it is possible to immunologically target the abnormal protein conformation that underlies the pathogenesis of many neurodegenerative disorders with minimal or no risk of inducing a deleterious autoimmune reaction. Such an approach has the potential added advantage of addressing the pathological deposition of more then one protein/peptide concurrently.
O2-05-04
IMMUNE SYSTEM RECONSTITUTION REDUCES Ab/b-AMYLOID PATHOLOGY IN PSAPP MICE
Jun Tan1, Yuyan Zhu1, Damien Oregon1, Huayan Hou1, Deyan Luo1, Takashi Mori2, Brian Giunta1, Yangbing Zhao3, Terrence Town4, 1Univer-
P113
sity of South Florida, Tampa, FL, USA; 2Saitama Medical Center, Tokyo, Japan; 3School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 4Cedars-Sinai Medical Center, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: Mutations in the presenilin-1 (PS1) gene are causally linked to familial early-onset Alzheimer’s disease (AD). Previous studies have shown alterations in immune function in AD patients, raising the possibility that PS1 plays a role in regulation of immunity. In support of this, mutant human PS1 (both M146V and PSEN1dE9) mice exhibit abnormal T- and B-cell immune responses. Methods: To test whether PS1-associated abnormality in immune function could modify AD-like pathology, we reconstituted the immune system with bone marrow cells (BMC) in two different AD mouse models: PSAPP [bearing both mutant human APP (K670N, M671L) and mutant human PS1 (PSEN1dE9) transgenes] and Tg2576 [carrying mutant APP (K670N, M671L) alone]. Results: Here, we report a marked reduction of Ab levels/b-amyloid plaques and associated inflammation in PSAPP mice following strainmatched wild-type bone marrow infusion. Strikingly, Tg2576 mice showed accelerated AD-like pathology following PS1 mutant mousederived BMC infusion. Most importantly, these effects were associated with altered markers of immune function. Conclusions: These data show that hematopoetic cells bearing the mutant human PS1 transgene, an independent genetic cause of familial AD, exacerbate AD-like pathology in AD mouse models, suggesting a novel immunomodulatory therapeutic strategy for AD.
O2-05-05
RESULTS OF THE FIRST-IN-MAN STUDY WITH THE ACTIVE Ab IMMUNOTHERAPY CAD106 IN ALZHEIMER PATIENTS
Bengt G. Winblad1, L. Minthon2, A. Floesser3, G. Imbert3, T. Dumortier3, ¨ stlund2, J. Lundmark5, Y. He4, P. Maguire3, M. Karlsson2, H. O J. M. Orgogozo6, A. Graf3, N. Andreasen7, 1Karolinska Institutet, Huddinge, Sweden; 2Universitetssjukhuset MAS, Malmo¨, Sweden; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals, Cambridge, MA, USA; 5 Novartis Pharma Sweden, Stockholm, Sweden; 6University of Bordeaux, Bordeaux, France; 7Karolinska Universitetssjukhuset, Huddinge, Sweden. Contact e-mail: [email protected] Background: CAD106 is an immunotherapeutic vaccine comprising the Aß1-6 peptide coupled to the Qß virus-like particle. In animals, CAD106 induced Aß-antibody titers without activating Aß-reactive T-cells. Administration of CAD106 to APP transgenic mice showed a reduction of amyloid accumulation in the brain. Methods: Safety, tolerability and immunogenicity of CAD106 was assessed in a first-in-man study CCAD106A2101, a 52week, two-center, randomized, double-blind, placebo-controlled, parallel group study in patients with mild to moderate AD in Sweden. Patients were administered 50ug CAD106/placebo at weeks 0/6/18 in Cohort I, and 150ug CAD106/placebo at weeks 0/2/6 in Cohort II. Results: 58 Caucasians (30m, 28f) with MMSE 16-26 were randomized in two semi-overlapping cohorts. Results of Cohort I were presented previously. The mean age was 69.3 and 68 years in Cohort I and II, respectively. One Cohort II patient discontinued the study due to withdrawal of consent at week 26. No cases of meningoencephalitis were detected clinically, and no relevant concerns were raised by the repeated CSF and MRI assessments. Adverse events were predominantly mild. Between the cohorts, an increase in injection-related reactions was observed in patients receiving CAD106, with the most common reaction being injection-site erythema (CAD106 Cohort I: 4%; vs CAD106 Cohort II: 64%). Serious adverse events were reported in Cohort I for 4/24 (17%) patients on CAD106 and 1/7 (14%) on placebo, and in Cohort II for 4/22 (18%) patients on CAD106 and none on placebo. All SAEs were considered unrelated to the study medication by the investigator and the DSMB. CAD106 induced a measurable specific antibody response against Aß in 16/24 Cohort I patients and in 18/22 Cohort II patients. Peak mean Aß IgG antibody titers were observed at week 8 in both cohorts with a 2-fold increase observed in Cohort II. Exploratory
O2-05-03
IMMUNOTHERAPY TARGETING ABNORMAL PROTEIN CONFORMATION
Thomas Wisniewski1, Frances Prelli1, Henrieta Scholtzova1, Erika Chung1, Pankaj D. Mehta2, Regina Kascsak2, Richard Kascsak2, Fernando Goni1, 1 NYU School of Medicine, New York, NY, USA; 2New York Staten Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease is the most common of the conformational neurodegenerative disorders, where the pathogenesis is linked to a normal protein undergoing a shape change into a pathological conformer with a high b-sheet content. In the case of AD this involves both amyloid b and abnormally phosphorylated tau forming toxic oligomeric structures. In the case of another conformational disorder, the prion diseases, the pathogenesis is linked to a change in the cellular prion protein (PrPC) into the disease associated PrPSc. Currently there is no effective therapy for any of these disorders. However, immunomodulation holds great promise. Major problems with this approach include: the potential of toxicity from neuroinflamation related to excessive cell mediated autoimmunity and the immunological targeting of both the normal and abnormal Ab peptide. In addition, tau related pathology has not been addressed. Methods: We have developed a novel immunotherapeutic approach that may potentially overcome many of these weaknesses. We used active immunization with aggregated British amyloid (ABri) related peptides. This rare form of familial human amyloidosis is associated with a mis-sense mutation in a stop codon resulting in the production of a highly amyloidogenic protein with no sequence homology to other native human proteins. Results: Our preliminary data indicates that mice immunized with aggregated/oligomerized preparations of ABri recognized heterologous amyloid structures including oligomeric Ab and PrPSc. Monoclonal antibodies were derived from successfully vaccinated animals and interestingly some of them recognize oligomeric Aß but not monomeric Ab, as well as paired helical filaments and PrPSc. ABri has no sequence homology with Ab, tau or PrP; hence, this immune response is not amino acid sequence specific but represents a preferential targeting of the pathological protein/peptide conformations shared by Ab, tau and PrPSc. We also show that active immunization of APP/PS1 AD Tg mice with ABri produces significant cognitive benefits. Conclusions: Our results suggest that it is possible to immunologically target the abnormal protein conformation that underlies the pathogenesis of many neurodegenerative disorders with minimal or no risk of inducing a deleterious autoimmune reaction. Such an approach has the potential added advantage of addressing the pathological deposition of more then one protein/peptide concurrently.
O2-05-04
IMMUNE SYSTEM RECONSTITUTION REDUCES Ab/b-AMYLOID PATHOLOGY IN PSAPP MICE
Jun Tan1, Yuyan Zhu1, Damien Oregon1, Huayan Hou1, Deyan Luo1, Takashi Mori2, Brian Giunta1, Yangbing Zhao3, Terrence Town4, 1Univer-
P113
sity of South Florida, Tampa, FL, USA; 2Saitama Medical Center, Tokyo, Japan; 3School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 4Cedars-Sinai Medical Center, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: Mutations in the presenilin-1 (PS1) gene are causally linked to familial early-onset Alzheimer’s disease (AD). Previous studies have shown alterations in immune function in AD patients, raising the possibility that PS1 plays a role in regulation of immunity. In support of this, mutant human PS1 (both M146V and PSEN1dE9) mice exhibit abnormal T- and B-cell immune responses. Methods: To test whether PS1-associated abnormality in immune function could modify AD-like pathology, we reconstituted the immune system with bone marrow cells (BMC) in two different AD mouse models: PSAPP [bearing both mutant human APP (K670N, M671L) and mutant human PS1 (PSEN1dE9) transgenes] and Tg2576 [carrying mutant APP (K670N, M671L) alone]. Results: Here, we report a marked reduction of Ab levels/b-amyloid plaques and associated inflammation in PSAPP mice following strainmatched wild-type bone marrow infusion. Strikingly, Tg2576 mice showed accelerated AD-like pathology following PS1 mutant mousederived BMC infusion. Most importantly, these effects were associated with altered markers of immune function. Conclusions: These data show that hematopoetic cells bearing the mutant human PS1 transgene, an independent genetic cause of familial AD, exacerbate AD-like pathology in AD mouse models, suggesting a novel immunomodulatory therapeutic strategy for AD.
O2-05-05
RESULTS OF THE FIRST-IN-MAN STUDY WITH THE ACTIVE Ab IMMUNOTHERAPY CAD106 IN ALZHEIMER PATIENTS
Bengt G. Winblad1, L. Minthon2, A. Floesser3, G. Imbert3, T. Dumortier3, ¨ stlund2, J. Lundmark5, Y. He4, P. Maguire3, M. Karlsson2, H. O J. M. Orgogozo6, A. Graf3, N. Andreasen7, 1Karolinska Institutet, Huddinge, Sweden; 2Universitetssjukhuset MAS, Malmo¨, Sweden; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals, Cambridge, MA, USA; 5 Novartis Pharma Sweden, Stockholm, Sweden; 6University of Bordeaux, Bordeaux, France; 7Karolinska Universitetssjukhuset, Huddinge, Sweden. Contact e-mail: [email protected] Background: CAD106 is an immunotherapeutic vaccine comprising the Aß1-6 peptide coupled to the Qß virus-like particle. In animals, CAD106 induced Aß-antibody titers without activating Aß-reactive T-cells. Administration of CAD106 to APP transgenic mice showed a reduction of amyloid accumulation in the brain. Methods: Safety, tolerability and immunogenicity of CAD106 was assessed in a first-in-man study CCAD106A2101, a 52week, two-center, randomized, double-blind, placebo-controlled, parallel group study in patients with mild to moderate AD in Sweden. Patients were administered 50ug CAD106/placebo at weeks 0/6/18 in Cohort I, and 150ug CAD106/placebo at weeks 0/2/6 in Cohort II. Results: 58 Caucasians (30m, 28f) with MMSE 16-26 were randomized in two semi-overlapping cohorts. Results of Cohort I were presented previously. The mean age was 69.3 and 68 years in Cohort I and II, respectively. One Cohort II patient discontinued the study due to withdrawal of consent at week 26. No cases of meningoencephalitis were detected clinically, and no relevant concerns were raised by the repeated CSF and MRI assessments. Adverse events were predominantly mild. Between the cohorts, an increase in injection-related reactions was observed in patients receiving CAD106, with the most common reaction being injection-site erythema (CAD106 Cohort I: 4%; vs CAD106 Cohort II: 64%). Serious adverse events were reported in Cohort I for 4/24 (17%) patients on CAD106 and 1/7 (14%) on placebo, and in Cohort II for 4/22 (18%) patients on CAD106 and none on placebo. All SAEs were considered unrelated to the study medication by the investigator and the DSMB. CAD106 induced a measurable specific antibody response against Aß in 16/24 Cohort I patients and in 18/22 Cohort II patients. Peak mean Aß IgG antibody titers were observed at week 8 in both cohorts with a 2-fold increase observed in Cohort II. Exploratory