* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Determinant-specific Amino Acid Copolymers Induce Innate
Germ theory of disease wikipedia , lookup
Behçet's disease wikipedia , lookup
Globalization and disease wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Herd immunity wikipedia , lookup
Social immunity wikipedia , lookup
Sociality and disease transmission wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Vaccination wikipedia , lookup
Neuromyelitis optica wikipedia , lookup
Adaptive immune system wikipedia , lookup
Gluten immunochemistry wikipedia , lookup
Immunocontraception wikipedia , lookup
Immune system wikipedia , lookup
Autoimmunity wikipedia , lookup
Innate immune system wikipedia , lookup
DNA vaccination wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Pathophysiology of multiple sclerosis wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Multiple sclerosis research wikipedia , lookup
Molecular mimicry wikipedia , lookup
Eric Zanelli, PhD Bethesda, March 5, 2010 Induction of an anti-inflammatory immune response toward toxic species of alpha-synuclein IMMUNOMODULATORY THERAPY FOR PARKINSON’S DISEASE 1 PEPTIMMUNE CONFIDENTIAL Parkinson’s Disease Parkinson’s disease (PD) is a neurodegenerative disease with loss of dopamine-containing neurons in the substantia nigra Suggested causes of PD include: – Mitochondrial dysfunction – Oxidative stress – Impaired protein degradation processes (misfolded a-synuclein) Additionally, immune system involvement is established (either primary or secondary) – Innate immunity – Adaptive immunity PD patients would benefit from an immunotherapy that – Clears toxic oligomers and protofibrils through a-syn-specific antibodies – Induces monocytes/microglia with anti-inflammatory phenotype 2 PEPTIMMUNE CONFIDENTIAL Immunomodulatory Approach for PD Target Product Profile: – First-line disease modifying treatment – Weekly or bi-weekly subcutaneous administration in a pre-filled syringe/auto-injector – Exhibit excellent long-term safety and tolerability profile enjoyed by marketed copolymers such as Copaxone™ (Teva) Dual Mechanisms of Action: – Induces antibody-mediated clearance of post-translationally modified, toxic alpha-synuclein oligomers and protofibrils found in PD patients – Induces an immunoregulatory, neuroprotective immune response capable of dampening inflammatory microenvironments found in PD patients 3 PEPTIMMUNE CONFIDENTIAL Amino Acid Copolymer Platform DEEP: Directed Expansion of Epitope Permutations What is an amino acid copolymer? A single manufacturing peptide entity comprising multiple related antigenic determinants Promiscuous MHC class II binding Enhanced immunogenicity Broad Application Immune Modulating Copolymer Epitope specific copolymer Specific Antigenic Determinant 4 PEPTIMMUNE CONFIDENTIAL Therapeutic vaccines for various disorders Prophylactic vaccines against highly mutating infectious agents Ligands for antibody screening Immune System Involvement in Parkinson’s Disease In Mouse In Man Th17 cells CD4+ and CD8+ T cells – promote neurodegeneration in MPTP model, Reynolds et al, J Immunol (2010) 184:2261 Vasoactive Intestinal peptide (VIP) – induces Treg which attenuate microglia-mediated inflammation, Reynolds et al, J Immunol (2010) 184:2261 – ten-fold increase in substantia nigra in PD patients as compared to age-matched controls, Brochard et al, J Clin Invest (2009) 119:182 Pro-inflammatory markers – Increased production of MCP-1, IL-8, IFNg, TNFa by PBMCs from PD patients, FasL+ CD4+ T cells – contribute to neurodegeneration in MPTP model, Brochard et al, J Clin Invest (2009) 119:182 5 PEPTIMMUNE CONFIDENTIAL Reale et al, Brain Behav Immun (2009) 23:55 The Copaxone/PI-2301 Experience 6 Copaxone™ PI-2301 Approved by FDA in 1996 for treatment of RR-MS 20-200 amino acid long peptides made of Y, E, A and K Limited effect on monocytes Induces regulatory T-cell response Limited bioavailability Suspected neuroprotective effect? Phase II in RR-MS initiated 52-amino acid-long peptides made of Y, F, A and K Improved MHC class II binding Induction of antiinflammatory response in man demonstrated Better preclinical efficacy Better effect on monocytes Improved bioavailability (N-terminal acetylation) PEPTIMMUNE CONFIDENTIAL Copaxone in Animal Models of Neurodegeneration Copaxone-specific T-cells protect mice from MPTP toxicity Benner et al, Proc Natl Acad Sci USA (2004) 101:9435 – Effect results in markedly decreased activation of microglia – Increased expression of Glial cell-Derived Neutrophic Factor (GDNF) might play a role Copaxone vaccination reduces b amyloid accumulation in APP/PS1 transgenic mice Butovsky et al, Proc Natl Acad Sci USA (2006) 103:11784 – Induction of phenotype switch in microglia – Increased production of Insulin-like Growth Factor-1 (IGF-1) by microglia 7 PEPTIMMUNE CONFIDENTIAL Decreased Production of pro-inflammatory Cytokines by Macrophages cultured with PI-2301 IL-6 concentration in culture supernatant of bone marrow-derived macrophages - Study day 9 - TNFa concentration in culture supernatant of bone marrow-derived macrophages - Study day 9 2750 15,000 2500 [TNFa ] culture supernatant (pg/mL) [IL-6] culture supernatant (pg/mL) 12,500 10,000 7,500 5,000 2250 2000 1750 1500 1250 2,500 Copaxone PI-2301 1000 PLP139-151 0 0 3 6 9 12 0 [Compound] (M) 3 6 9 [Compound] (M) PEPTIMMUNE CONFIDENTIAL 12 Immune Response alone will not work Concept of vaccine therapy for neurodegenerative diseases is currently tested in man – Anti-b amyloid (Ab) trials through either active or passive immunization in Alzheimer – 6% of Alzheimer’s patients treated with AN1792 in Phase IIa (study 201) developed meningoencephalitis, Pride et al, Neurodegener Dis (2008) 5:194 – T-cell response to Ab peptide was characterized as Th1 in contrast to Th2 response observed in study 102 • Changes in formulation? – Antibody responses in both studies were similar – Use of adjuvant QS-21 probably promoted the Th1 response Importance of maintaining the correct Th2 response as induced by Copaxone or PI-2301 9 PEPTIMMUNE CONFIDENTIAL Proposed Design for a-syn Amino Acid Copolymer Tri-nitrations Target Region: a-syn 121-137 DNEAYEMPSEEGYQDYE Species Alterations Immune response targeted at a 17-amino acid region, Specificity for toxic species guaranteed through use of phosphorylated Ser (S) and nitrated Tyr (Y), Substitutions incorporated to account for interspecies variabilities, Immunogenicity guaranteed by % Ala (A) incorporation at every position and compound length through tandem-repeats of the same region, Tyr (Y) and Glu (A) also found in Copaxone provide anchoring residues to various MHC class II molecules and T-cell help, Goal is to induce specific immune response to toxic species of a-syn, only • • 10 Phosphorylation without need for strong adjuvant, while preserving anti-inflammatory properties found in Copaxone and PI-2301. PEPTIMMUNE CONFIDENTIAL A testable hypothesis a-synuclein amino acid copolymer induces: In vitro – An expansion of anti-inflammatory monocytes and/or T-cells with regulatory properties, – Antibodies capable of clearing misfolded protein deposits. ASO Mice – A reduction in alpha-synuclein burden, – Specific effects on motor and olfactory measurements in ASO mice, – Alterations in striata and ventral midbrain. MPTP-induced Toxicity – From: SH Appel, J Clin Invest (2009) 119:13 11 PEPTIMMUNE CONFIDENTIAL Protection of nigrostriatal pathway.