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Presentation The Clinical Potential of the Human Plasma Proteome Leigh Anderson Ph.D. Founder & CEO, Plasma Proteome Institute Board Member, Dade Behring PPI The Plasma Proteome Institute Plasma is the largest, and deepest, version of the human proteome • Largest = Most proteins • Deepest = Widest dynamic range PPI Website Oct 2002 © Plasma Proteome Institute PPI Major Components of the Plasma Proteome • ~40,000 forms of proteins secreted to function in “Plasma Cellular Proteins plasma, most glycoproteins Proteins” (Leakage) – Assume 500 gene products x 2 splice variants x 20 glycoforms x 2 clip forms • ~500,000 forms of tissue proteins – Essentially all tissue proteins Immunoglobulins x splice and PTM variants • ~10,000,000 clonal forms of immunoglobulin Total: the largest version of the human proteome PPI Website Oct 2002 © Plasma Proteome Institute PPI A New Functional Classification of Proteins in Plasma 1. Secreted proteins that act in plasma (e.g., albumin, fibrinogen) 2. Immunoglobulins (Ig’s A,M,G,D,E) 3. Tissue leakage products (e.g., cardiac Mb) 4. “Distant” receptor ligands (e.g.,insulin) 5. “Local” receptor ligands (e.g., IL-8) 6. Aberrant secretions (e.g., PSA in cancer) 7. Temporary passengers (e.g., lysosomal enz.) 8. Foreign proteins (e.g., virus) PPI Website Oct 2002 © Plasma Proteome Institute PPI Major Plasma Proteins 99% of plasma protein mass Fibrinogen Transferrin IgA Total C4 Complement Complement Factor B Alpha-2-Macroglobulin Ceruloplasmin Prealbumin IgG Total IgM Total C9 Complement Alpha-1-Antitrypsin Factor H C3 Complement C1q Complement C8 Complement Haptoglobin Lipoprotein(a) 1% 10% Alpha-1-acid Glycoprotein Apolipoprotein A-1 Albumin Apolipoprotein B 0 - 90% 90 - 99% PPI Website Oct 2002 © Plasma Proteome Institute PPI © Plasma Proteome Institute © Plasma PPI Website Oct 2002 Normal Range Abundances Proteins Measured ClinicallyinPlasmaSpan Log10 Concentration in pg/mL 10 11 12 > 10OrdersofMagnitude inAbundance 0 1 2 3 4 5 6 7 8 9 *Hemoglobin* Clas Albumin Other Interleukins &Cytokines Tissue Leakage IgG Total Transferrin Fibrinogen IgA Total sic Alpha-2-Macroglobulin IgM Total a Alpha-1-Antitrypsin l P C3 Complement Haptoglobin l Apolipoprotein A-1 as Apolipoprotein B Alpha-1-acid Glycoprotein ma P Lipoprotein(a) Factor H Ceruloplasmin C4 Complement r Complement Factor B o (Human m Prealbumin t C9 Complement eins C1q Complement C8 Complement C5 Complement Plasminogen a le IgD C1 Inhibitor 50yr - C6 Complement C7 Complement Complement Factor I f Retinol Binding Protein rom Spec iC3b Thyroxin Binding Globulin C2 Complement Protein Thrombus Precursor Protein C-reactive Protein ialt Bb Fragment C3a Complement Protein y L Ferritin aboratories Rantes SC5b-9 Complex Myoglobin Thyroglobulin TPA C5a Complement Neuron-Specific Enolase Books) C-Peptide Alpha-fetoprotein TNF-Binding Proteins Total Cost:$10,695 Prostate-Specific Antigen proteomic tech Dynamic rangeofsingle Prostatic Acid Phosphatase CEA Myelin Basic Protein Troponin I per sample Interleukin-1ra MIP-1 beta Troponin T Interleukin-8 MIP-1 alpha Tissue Factor PPI GCSF Interferon Alpha Interleukin-2 n i Interleukin-4 qu TNF-Alpha Interferon Gamma es Interleukin-1 Beta Interleukin-12 Interleukin-10 Interleukin-5 Interleukin-6 Plasma “Proteomics” Began With 2-D Gels (c. 1976) 2-D Electrophoresis 300+ resolved spots 40 identified proteins Anderson,L., Anderson,N. G. High resolution two-dimensional electrophoresis of human plasma proteins. (1977) PNAS 74, 5421-5 PPI Website Oct 2002 © Plasma Proteome Institute PPI Short History Most protein technologies have been applied to plasma rapidly Year Event 1933 Von Mutzenbacher uses Svedberg’s analytical ultracentrifuge to resolve serum albumin and globulin fractions by molecular weight: demonstrates proteins are not heterogeneous colloids but rather specific structures 1937 Tiselius uses his electrophoresis to resolve serum proteins into α, β, and γ globulins, establishing a naming convention that still persists 1939 Tiselius and Kabat demonstrate that antibodies are components of the γ globulin fraction 1940’s Svensson and Longsworth further resolve serum globulins into α1, α2, β1, β2, γ1 and γ2 1950 Gofman finds lipoproteins float in ultracentrifuge and can be measured clinically 1950’s Paper electrophoresis of serum proteins is widely introduced into clinical chemistry 1958 Smithies and Poulik resolve 22 zones of serum proteins using starch gel electrophoresis 1960 Grabar and Burtin describe immunoelectrophoresis 1964 Ornstein and Davis introduce acrylamide ‘disc’ gel electrophoresis with resolution even higher than starch 1965 Laurell introduces crossed immunoelectrophoresis, resolving more than 40 different serum proteins 1966 Laurell introduces quantitative “rocket” electrophoresis 1977 Anderson and Anderson use 2-D electrophoresis to resolve hundreds of serum protein forms (40 identifications via immunoprecipitation) 1991 Published 2-D plasma protein database with 49 identified proteins and 727 spots 2002 Current SWISS-2D PAGE database with 60 identified proteins and est. 1500 spots 2002 Immunosubtraction/chromatography/2-DE with >250 identified proteins and est. 1000- 1500 spots (Pieper, et al, manuscript in preparation) PPI Website Oct 2002 © Plasma Proteome Institute PPI Growth in the Number of Protein Species Observed in Plasma Over Time 10000 “3+-D” Number of Zones/Spots Sequence Identified Unique Proteins “2-D” 1000 490+ 250* 100 “1-D” 49 60 40 10 Log10 Number of Resolved Species 1 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 Year PPI Website Oct 2002 * R. Pieper et al, manuscript in preparation © Plasma Proteome Institute + J.N. Adkins, in press PPI 5'-Nucleotidase Collagen III c-terminal propeptide Growth Hormone Binding Protein Neuron-specific Enolase Acid labile subunit of IGFBP Collagen III n-terminal propeptide Haptoglobin alpha-1 Neutrophil-activating peptide 2 Acid phophatase, tartrate-resistant Collagen IV 7S n-terminal propeptide Haptoglobin alpha-2-chain Osteocalcin Acid phosphatase, prostatic Complement C1 Inhibitor Haptoglobin beta chain Osteonectin Haptoglobin beta chain, cleaved Actin beta (from platelets) Complement C1q, A Pancreatic zymogen granule membrane Actin gamma (from platelets) Haptoglobin-related gene product Complement C1q, B Hemoglobin, alpha protein GP-2 Adenosine Deaminase Complement C1q, C Adiponectin Hemoglobin, beta Paraoxonase Parathyroid Hormone A Provisional Alanine aminotransferase (ALT) Complement C1r Hemopexin (Beta-1B-glycoprotein) Parathyroid Hormone-Related Protein Albumin Complement C1s Histidine-rich Alpha-2-glycoprotein PASP Aldolase (muscle type) Complement C2 ICAM-1, soluble Pepsinogen A Plasma Alkaline Phosphatase (bone) Complement C3A anaphylotoxin Ig Kappa light chain Plasma hyaluronan binding protein Alpha1,3-fucosyltransferase (FUT6) Complement C3B, alpha' Ig Lambda light chain Plasma kallikrein Complement C3B, beta IgA1 Plasma serine protease inhibitor Alpha-1-acid Glycoprotein IgA2 Proteome: Alpha-1-Antichymotrypsin Complement C4 anaphylotoxin IgD Plasminogen Alpha-1-Antitrypsin Complement C4, alpha IgE Plasminogen Alpha-1-B Glycoprotein Complement C4, beta IGFBP-3 Platelet Factor 4 Alpha-1-Microglobulin Complement C4, gamma IgG1 Pre-alpha trypsin inhibitor, H3 Alpha-2-Antiplasmin Complement C4-binding protein, alpha IgG2 Pregnancy-associated plasma protein-A 289 Proteins Alpha-2-HS Glycoprotein Complement C4-binding protein, beta IgG3 Pregnancy-associated plasma protein-A2 Alpha-2-Macroglobulin Complement C5A anaphylotoxin IgG4 Pregnancy-specific beta-1-glycoprotein 3 Alpha-fetoprotein Complement C5B, alpha' IgJ-chain Amylase (pancreatic) Prolactin Observed in Complement C5B, beta IgM Prolyl hydroxylase, alpha Angiostatin Inhibin (activin), beta A Angiotensin converting enzyme (ACE) Complement C6 Inhibin (activin), beta B Prolyl hydroxylase, beta Plasma Angiotensinogen Complement C7 Inhibin (activin), beta C Prostaglandin-H2 D-isomerase Antithrombin III (AT3) Complement C8, alpha Inhibin (activin), beta E Prostate Specific Antigen Apolipoprotein A-I Complement C8, beta Inhibin, alpha Protein C, H (Scientific Apolipoprotein A-II Complement C8, gamma Insulin C-Peptide Protein C, L Apolipoprotein A-IV Complement C9 Insulin, A chain Protein S Literature Apolipoprotein B-100 Complement Factor B Insulin, B chain Protein Z Apolipoprotein B-48 Complement Factor B - Bb Fragment Insulin-like growth factor IA P-selectin, soluble Apolipoprotein C-I Complement Factor D Insulin-like growth factor II Rantes Apolipoprotein C-II Inter-alpha trypsin inhibitor, H1 pre-2002) Complement Factor H Inter-alpha trypsin inhibitor, H2 Renin Apolipoprotein C-III Complement Factor I Retinol Binding Protein Apolipoprotein C-IV Inter-alpha trypsin inhibitor, H4 Connective Tissue Activating Peptide III Inter-alpha-trypsin inhibitorL S100 protein Apolipoprotein D Corticotropin Releasing Hormone (CRH) Apolipoprotein E Interferon Alpha Secretogranin V Apolipoprotein F C-reactive Protein Interferon Beta Serum Amyloid A Apolipoprotein H Creatine Kinase, B Interferon Gamma Serum Amyloid P Creatine Kinase, M Interleukin-1 Beta Sex Hormone Binding Globulin Apolipoprotein J (Clusterin) Interleukin-10 Almost none Apolipoprotein(a) CRHBP Tetranectin Cystatin C Interleukin-12, alpha Thyroglobulin Aspartate aminotransferase (AST) Interleukin-12, beta were discovered Beta Thromboglobulin Elastase (neutrophil) Interleukin-1receptor antagonist Thyroid Stimulating Hormone Beta-2-microglobulin Eosinophil granule major basic protein Interleukin-2 Thyrotropin-releasing hormone CA 125 E-selectin,
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