PRODUCTS. Autoimmune Disease Antigens. Custom Design Antigens. Infectious Disease Antigens

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1 T H E E X P E R T S O N Y O U R S I D E Antigen Catalog

2 PRODUCTS Autoimmune Disease Antigens Outstanding assay performance with the most complete panel of recombinant and native autoimmune antigens for all diagnostic applications. Custom Design Antigens Purified recombinant proteins from the specialists for baculovirus / insect cell and E. coli bacterial expression. Infectious Disease Antigens The newest product line, manufactured according to the the customary quality guidelines of DIARECT antigens.

3 Contents Page Page Autoimmune Disease Antigens Customer Service Autoimmune Thyroid Diseases 2 Quality Management 34 Mixed Connective Tissue Disease / Lot-to-lot Consistency 36 Systemic Lupus Erythematosus 4 Reservation System 37 Systemic Lupus Erythematosus 6 Ordering & Shipping 38 Systemic Lupus Erythematosus 8 AUTOIMMUNE DISEASES Sjøgren s Syndrome / Systemic Lupus Erythematosus 10 Index 40 Systemic Sclerosis / CREST Syndrome 12 Polymyositis / Dermatomyositis 14 Celiac Disease 16 ANCA Associated Diseases 18 Autoimmune Hepatitis 20 Primary Biliary Cirrhosis 22 INFECTIOUS DISEASES Antiphospholipid Syndrome / Thromboembolic Syndrome / Goodpasture s Syndrome 24 Pernicious Anemia / Crohn s Disease 26 Infectious Disease Antigens Lyme Disease 28 Erythema infectiosum 30 CUSTOM DESIGN Custom Design Antigens Your Antigen / Design 32 Upstream / Downstream

4 AUTOIMMUNE DISEASES Autoimmune Thyroid Diseases Autoantibodies to thyroid peroxidase (TPO), an integral membrane protein of the apical surface of thyroid epithelial cells, are characteristic of autoimmune thyroid disease in humans. These IgG antibodies, formerly known as thyroid microsomal antibodies, are associated with thyroid destruction, hypothyroidism, and lymphocytic thyroiditis (Graves disease). Most patients with autoimmune thyroid diseases, especially chronic Hashimoto s thyroiditis also produce autoantibodies to thyroglobulin, the main component of the colloid in the thyroid follicle

5 Thyroid Peroxidase (TPO) Autoimmune Thyroiditis Thyroglobulin (non recombinant) Autoimmune Thyroiditis non recombinant human, native Product Product AUTOIMMUNE DISEASES CUSTOM DESIGN INFECTIOUS DISEASES - 3 -

6 AUTOIMMUNE DISEASES Mixed Connective Tissue Disease / Systemic Lupus Erythematosus Mixed connective tissue disease (MCTD) was originally described as a syndrome that consisted of a combination of features typically found in patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis / dermatomyositis (PM/DM), or rheumatoid arthritis. The characteristic serologic features that permitted differentiation of MCTD from other connective tissue diseases (CTDs) were high-titer antinuclear antibodies with a speckled IFA pattern and the presence of U1-snRNP specific autoantibodies. Antibody titers to U1-snRNP specific targets (68/70 kda, A, and C antigens) are usually higher in MCTD sera than in SLE sera. High frequencies of Raynaud s phenomenon and anti-u1-snrnp, but low frequencies of nephritis and anti-sm are characteristic of MCTD (with inversely related frequencies in SLE)

7 U1-snRNP 68/70 kda MCTD / SLE expressed in E. coli Product AUTOIMMUNE DISEASES U1-snRNP A MCTD / SLE U1-snRNP C Product INFECTIOUS DISEASES MCTD / SLE Product U-snRNP B/B CUSTOM DESIGN MCTD / SLE Product

8 AUTOIMMUNE DISEASES Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that affects multiple organ systems and is characterized by a range of symptoms, including kidney disease, arthritis, cardiopulmonary abnormalities, and skin photosensitivity. Anti-Sm antibodies are highly specific for SLE and are therefore recorded in the classification criteria of the American College of Rheumatology. Anti-Sm antibodies are found in 5 to 30% of patients with SLE, the frequency varying on the detection system and the selection criteria for study cohorts. Also, a racial difference in the incidence of anti-sm antibodies has been shown. The Sm antigen is part of the spliceosomal complex catalyzing the splicing of nuclear pre-mrna. Each spliceosome snrnp consists of snrnas (U1, U2, U4 / U6, and U5) bound to a unique set of proteins as well as a shared set of seven different Sm proteins (typically SmB/SmB, SmD1, SmD2, SmD3, SmE, SmF, SmG). Most frequently the SmB and SmD polypeptides are targets of the anti-sm specific autoimmune response, of which SmD is regarded the most SLE-specific Sm antigen

9 Sm (non recombinant; bovine) SLE non recombinant bovine Product AUTOIMMUNE DISEASES RNP/Sm (non recombinant; bovine) SmD SLE non recombinant bovine in preparation SmD1 Product SLE SmD2 Product INFECTIOUS DISEASES SLE ; symmetrically methylated SmD3 Product SLE Product CUSTOM DESIGN SLE ; symmetrically methylated Product

10 AUTOIMMUNE DISEASES Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation that results in the production of antinuclear antibodies, generation of circulating immune complexes, and activation of the complement system. Antibodies to doublestranded DNA are the serological feature of systemic lupus erythematosus. They are diagnostically and prognostically significant and play an important role in the pathogenesis of lupus nephritis, a major cause of morbidity and mortality in this disease. Besides the classical lupus autoantibodies like antidsdna and anti-sm, there is a range of additional albeit rare antigenic targets which also may be of crucial diagnostic importance. Autoantibodies toward the three ribosomal phosphoproteins P0, P1, and P2 are highly specific serological markers for SLE and may indicate CNS involvement. This is also true for anti- PCNA, a rare specificity, but when present should alert the clinician to the presence of defined or evolving SLE. On the other hand, anti-ku may be associated most strongly with SLE and overlap syndromes but is also present in myositis and scleroderma. Furthermore, preliminary clinical data with recombinant nucleolin show specific reactions of sera from patients with SLE and systemic sclerosis, respectively

11 dsdna (plasmid) SLE plasmid E. coli Product AUTOIMMUNE DISEASES Ribosomal Phosphoprotein P0 SLE Ribosomal Phosphoprotein P2 Product Ribosomal Phosphoprotein P1 SLE Proliferating Cell Nuclear Antigen (PCNA) Product INFECTIOUS DISEASES SLE Product SLE Product Ku (p70/p80) Nucleolin CUSTOM DESIGN Myositis / Scleroderma Overlap / SLE Pulmonary Hypertension Product SLE Product

12 AUTOIMMUNE DISEASES Sjøgren s Syndrome / Systemic Lupus Erythematosus Sjøgren s syndrome is an autoimmune disorder characterized by lymphocytic infiltrates and destruction of the salivary and lacrimal glands. Typical for this disease is the systemic production of autoantibodies to a ribonucleoprotein particle, which consists of the proteins Ro/SS-A (60 kda and 52 kda), La/SS-B (48 kda) and small cytoplasmic RNAs known as hy RNAs. The disease is referred to as primary Sjøgren s syndrome when it occurs alone and as secondary Sjøgren s syndrome when it occurs together with other connective tissue diseases like SLE. Anti-Ro and anti-la autoantibodies occur in high percentage of patients with SLE and Sjøgren s syndrome, respectively. In lupus patients, these antibodies are highly associated with photo - sensitive skin lesions, particularly those of subacute, cutaneous LE and also with neonatal lupus syndrome

13 Ro/SS-A (60 kda; recombinant) Sjøgren s Syndrome SLE / SCLE / Neonatal LE expressed in E.coli Product AUTOIMMUNE DISEASES Ro/SS-A (60 kda; non recombinant; bovine) Sjøgren s Syndrome SLE / SCLE / Neonatal LE non recombinant bovine Ro/SS-A (52 kda) Sjøgren s Syndrome SLE / SCLE / Neonatal LE La/SS-B Product Product INFECTIOUS DISEASES CUSTOM DESIGN Sjøgren s Syndrome SLE / SCLE / Neonatal LE Product

14 AUTOIMMUNE DISEASES Systemic Sclerosis / CREST Syndrome Systemic sclerosis (SSc) is a generalized disorder of connective tissue affecting skin and internal organs, characterized by fibrotic arteriosclerosis of peripheral and visceral architecture. Variable degrees of extra - cellular matrix accumulation (mainly collagen) occur in both skin and viscera and is very often associated with specific autoantibodies, most notably anticentromere and anti-scl-70 (autoantibodies against DNA topoisomerase I). Another type of autoantibodies anti-pm/scl is known to characterize a subset of autoimmune patients with myositis, scleroderma, and the PM/Scl overlap syndrome. Systemic features of scleroderma may include fibrosis and degeneration of the heart, lungs, kidneys and gastrointestinal tract. CREST syndrome, a limited form of SSc, is characterized by the following clinical features: Calcinosis cutis, Raynaud s phenomenon, Esophageal dysfunction, Sclerodactyly, and Teleangiectasia

15 Centromere Protein B (CENP-B) Systemic Sclerosis CREST Syndrome Product AUTOIMMUNE DISEASES Centromere Protein A (CENP-A) DNA Topoisomerase I (Scl-70; full length) Systemic Sclerosis CREST Syndrome DNA Topoisomerase I (Scl-70; truncated) Product Systemic Sclerosis Product DNA Topoisomerase I (Scl-70; non recombinant; bovine) INFECTIOUS DISEASES Systemic Sclerosis PM/Scl 100 Product Systemic Sclerosis non recombinant bovine in preparation PM/Scl 75 Product CUSTOM DESIGN Myositis / Systemic Sclerosis / Overlap Product Myositis / Systemic Sclerosis / Overlap Product

16 AUTOIMMUNE DISEASES Polymyositis / Dermatomyositis Inflammatory myopathies are characterized by the presence of inflammatory infiltrates within skeletal muscle. These idiopathic myopathies encompass a variety of both common and uncommon syndromes. The common subtypes include adult polymyositis (PM) and dermatomyositis (DM), along with inclusion body myositis, childhood myositis, malignancy-associated myositis, and myositis in overlap with another auto - immune connective tissue disease. Autoantibodies to aminoacyl-trna synthetases are found in 30% of sera from patients with myositis. They are highly specific for this disorder and strongly associated with complicat ing lung disease. Anti-SRP autoantibodies are mainly associated with a syndrome of a necrotiz ing myopathy with cardiac involvement, severe prognosis and poor response to therapy. Anti- Mi-2 autoantibodies are considered specific serological markers of DM. Detected in about 20% of myositis sera they are proven markers for acute onset, good prognosis and good response to therapy

17 Histidyl-tRNA Synthetase (Jo-1) Anti-Synthetase Syndrome Myositis Product Threonyl-tRNA Synthetase (PL-7) Anti-Synthetase Syndrome Myositis Product AUTOIMMUNE DISEASES Alanyl-tRNA Synthetase (PL-12) SRP54 Anti-Synthetase Syndrome Myositis PM/Scl 100 Product Polymyositis PM/Scl 75 Product INFECTIOUS DISEASES Myositis / Systemic Sclerosis / Overlap Product Myositis / Systemic Sclerosis / Overlap Product Mi-2 CUSTOM DESIGN Dermatomyositis Myositis Product

18 AUTOIMMUNE DISEASES Celiac Disease Celiac disease is an inflammatory condition of the small intestine caused by an inappropriate immune response to the ingestion of certain dietary cereal proteins gliadins in genetically susceptible individuals. The pathogenesis of the disease involves interaction between environmental, genetic and immunological factors. The only treatment at present is lifelong strict adherence to a gluten-free diet, which enables intestinal mucosa to recover. The identification of tissue-type transglutaminase as the antigen toward which autoantibodies are directed has led to a greater understanding of the pathogenesis and to the development of improved serological tests

19 Tissue Transglutaminase (ttg; expressed in Baculovirus/Sf9) Celiac Disease Product AUTOIMMUNE DISEASES Tissue Transglutaminase (ttg; expressed in E. coli) Celiac Disease expressed in E.coli Gliadin (recombinant; deamidated) Product INFECTIOUS DISEASES Celiac Disease recombinant, deamidated expressed in E. coli Product CUSTOM DESIGN

20 AUTOIMMUNE DISEASES ANCA Associated Diseases The most well-known neutrophil-specific autoantibodies (ANCA) are those found in necrotizing small vessel vasculitis. These antibodies predominantly belong to the IgG class and give clear positive reactions by indirect immunofluorescence (IIF) on ethanol-fixed neutrophils and monocytes; their main targets are proteinase 3 (PR3), which results in the so-called cytoplasmic canca pattern, and myeloperoxidase (MPO). Anti-MPO antibodies are found in numerous sera that produce a perinuclear panca pattern. However, many sera exhibiting panca pattern by IIF do not contain antibodies to MPO. Antibodies directed against PR3 are a sensitive and specific marker for ANCA-associated vasculitis and, in particular, for Wegener s granulomatosis. The presence of anti-mpo in the right clinical context strongly suggests necrotizing vasculitis or idiopathic pauci-immune necrotizing and crescentic glomerulonephritis. Today the role of antineutrophil cytoplasmic antibodies in the clinical diagnostics of systemic inflammatory disease is still increasing. Their description dates back around some 30 years, and they have become an important criterion in routine vasculitis testing. The currently established method for the determination of ANCA is indirect immunofluorescence on human neutrophils and antigen-specific ELISA,line or multiplex assays

21 Myeloperoxidase (MPO; non recombinant) Microscopic Polyangiitis Idiopathic Crescentic Glomerulonephritis Churg-Strauss-Syndrome Classic Panarteritis Nodosa non recombinant human leukocytes Product AUTOIMMUNE DISEASES Proteinase 3 (PR3; non recombinant) Wegener s Granulomatosis non recombinant human leukocytes Product INFECTIOUS DISEASES BPI (non recombinant) ANCA target in diverse diseases non recombinant human leukocytes Product CUSTOM DESIGN

22 AUTOIMMUNE DISEASES Autoimmune Hepatitis Autoimmune hepatitis (AIH) is a disorder of unknown etiology responsible for a progressive destruction of the liver parenchyma. It has a high mortality rate if left untreated. One of the characteristics of this disease is the presence of circulating autoantibodies in almost 90% of patient s sera. Clinical and serological differences between patients lead to the classification of AIH into two types. Type 1 is characterized by the presence of smooth muscle antibodies and / or antinuclear antibodies whereas those from type 2 patients show anti-liver-kidney micro somal antibodies (LKM 1) and anti-liver-cytosol type 1 antibodies (LC 1). LC 1 auto - antibodies have been shown to be the only serological marker in 10% of AIH patients

23 Cytochrome P450 2D6 (LKM 1 hp) Autoimmune Hepatitis Type 2 Product AUTOIMMUNE DISEASES Formiminotransferase Cyclodeaminase (LC 1) Autoimmune Hepatitis Type 2 Product INFECTIOUS DISEASES CUSTOM DESIGN

24 AUTOIMMUNE DISEASES Primary Biliary Cirrhosis Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune liver disease involving obstruction of intra - hepatic bile ducts, which interferes with bile secretion, causing fibrosis and eventually cirrhosis of the liver. Clinical symptoms include fatigue, pruritis and jaundice. Antimitochondrial antibodies (AMA/M2) are present in % of cases of PBC long before clinical signs or symptoms appear. These include antibodies towards the E2 subunits (dihydrolipoamide transferases) of the pyruvate dehydrogenase complex (PDC-E2), branched chain 2-BCOADC dehydrogenase complex (BCOADC- E2), and 2-oxoglutarate dehydrogenase complex (OGDC-E2). Although M2 antibodies are considered the hallmark diagnostic feature of primary biliary cirrhosis (PBC), they are not the only disease-specific autoantibodies. A number of additional proteins have been identified such as the nuclear autoantigens Sp100, gp210 or Nup62. These nuclear autoantibodies are found in a subset of patients with PBC, including those who are AMA2-negative

25 M2 Primary Biliary Cirrhosis Product AUTOIMMUNE DISEASES BCOADC-E2 (M2 component) OGDC-E2 (M2 component) Primary Biliary Cirrhosis PDC-E2 (M2 component) Product Primary Biliary Cirrhosis Sp100 Product INFECTIOUS DISEASES Primary Biliary Cirrhosis Product Primary Biliary Cirrhosis Product gp210 Nup62 CUSTOM DESIGN Primary Biliary Cirrhosis Product Primary Biliary Cirrhosis Product

26 AUTOIMMUNE DISEASES Antiphospholipid Syndrome/ Thromboembolic Syndrome Antiphospholipid antibodies, comprising lupus anti - coagulants (LA) and anticardiolipin antibodies (acl) have been associated with thrombotic disease in patients with SLE or without any underlying disease (primary antiphospholipid syndrome; APS). The recently revised criteria for APS list three laboratory parameters: LA, acl, and β2-glycoprotein 1 (β2-gp1; Apolipoprotein H; Apo H) whereas at present the best-characterized antigenic target for these antibodies seems to be the phospholipidbinding protein β2-gp 1. Goodpasture s Syndrome Goodpasture s syndrome is a rare but serious auto - immune condition that can cause severe kidney and lung damage with rapidly progressive glomerulonephritis and pulmonary hemorrhage. The detection of auto - antibodies to glomerular basement membrane (anti- GBM) is an important part of a reliable diagnosis. The dominant epitope in the globular NC1 domain of α3 chain of type IV collagen is a so-called cryptotope, i.e. the antibodies preferentially bind to a denatured structure

27 β2-glycoprotein 1 (Apolipoprotein H) Primary / Secondary APS Product Glomerular Basement Membrane (GBM; dissociated) Goodpasture s Syndrome Product AUTOIMMUNE DISEASES β2-glycoprotein 1 (Apo H; non recombinant; human) Primary / Secondary APS non recombinant human Product INFECTIOUS DISEASES β2-glycoprotein 1 (Apo H; non recombinant; bovine) Primary / Secondary APS non recombinant bovine Product CUSTOM DESIGN

28 AUTOIMMUNE DISEASES Pernicious Anemia Pernicious anemia (PA) is an autoimmune disorder that causes neurological changes, including dementia. A condition of pernicious anemia is related to vitamin B12 deficiency, which occurs when autoantibodies to intrinsic factor or parietal cells reduce levels of intrinsic factor by interfering with its absorption. Crohn s Disease Crohn s disease (CD) and ulcerative colitis (UC) are the two most frequently occurring inflammatory bowel diseases in Caucasians. Mucosal inflammation in CD appears to occur when dysregulation of the immune system leads to an imbalance between tolerance to commensal microbiota or food-derived antigens and immunity to pathogens. It has been shown that autoimmune mechanisms play a role in the development of CD, and exocrine pancreas autoantibodies to glycoprotein 2 (GP2) are disease-specific. Also, autoanti - bodies to GP2 have been detected in 68% of Crohn s disease patients with extraintestinal complications such as idiopathic chronic pancreatitis

29 Intrinsic Factor Pernicious Anemia Product AUTOIMMUNE DISEASES GP2 Crohn s Disease Product INFECTIOUS DISEASES CUSTOM DESIGN

30 INFECTIOUS DISEASES Lyme Disease Lyme disease is a multisystemic infectious disease caused by Borrelia species. In the United States Borrelia burgdorferi is the main cause of Lyme disease, in Europe the most dominant species are Borrelia afzelii and Borrelia garinii. Another, even though relatively rare species is Borrelia spielmanii. Lyme disease is the most common tick-borne disease in the Northern Hemisphere. Borrelia is transmitted by the bite of infected ticks from the genus Ixodes. The various clinical manifestations in early disease stage include flu-like symptoms and a characteristic circular skin rash called erythema migrans. Left untreated, the disease is characterized by chronic infection of the joints, heart, and central nervous system. Delayed or inadequate treatment can lead to the serious, late manifestations, which can be disabling and difficult to treat

31 Products Recombinant Antigens Borrelia burgdorferi Borrelia burgdorferi p100 Borrelia burgdorferi p41 Borrelia burgdorferi OspC Borrelia burgdorferi DbpA Borrelia burgdorferi BmpA Borrelia burgdorferi DbpB Borrelia garinii Borrelia garinii p58 Borrelia spielmanii Borrelia spielmanii OspC Borrelia afzelii Borrelia afzelii DbpA Borrelia afzelii OspA Borrelia afzelii BmpA Whole Cell Detergent Extracts Borrelia burgdorferi Borrelia garinii Borrelia afzelii Product Product Product Product Product Product Product Product Product Product Product Product Product Product AUTOIMMUNE DISEASES INFECTIOUS DISEASES CUSTOM DESIGN Availability Lyme Disease

32 INFECTIOUS DISEASES Erythema infectiosum Parvovirus B19 is an infective disease agent for Erythema infectiosum, originally named fifth disease in an enumeration of childhood hemocytic rash diseases (measles, scarlet fever, German measles, Duke s disease, erythema infectiosum, and roseola). The virus is spread primarily by infected respiratory droplets. Seropositivity for past parvovirus B19 infection is high in the population, and serious, long-term complications are possible. Parvovirus B19 infections in pregnancy can lead to severe fetal anemia with miscarriage (about 10% of pregnancies) or serious damage to the fetus (hydrops fetalis). Virus replication in erythroid precursors worsens preexisting anaemic conditions and can lead to aplastic crisis. Arthritis complications have been described. As diagnostic tools DIARECT supplies viral capsids of parvovirus B19. One capsid product contains both the minor VP1 and major VP2 structural proteins, and a second product is a pure VP2 capsid

33 Parvovirus B19 VLP VP2 Erythema infectiosum recombinant Product AUTOIMMUNE DISEASES Parvovirus B19 VLP VP1/VP2 Co-Capsid Erythema infectiosum recombinant Product INFECTIOUS DISEASES CUSTOM DESIGN

34 CUSTOM DESIGN Your Antigen Design For customers requiring application-specific proteins in diagnostic products, DIARECT s recombinant protein expertise is available for development and production of customized proteins. Antigens from infectious disease agents, virus-like particles, calibrator material and designed fusion proteins are just a few examples of custom protein projects. Customer inquiries for custom proteins are handled under project- and quality-management guidelines. Since custom proteins may require protein engineering, the scientific literature supplies important background information for design of the exact target molecule and expression strategy. Once the target protein has been defined, DNA vectors for recombinant expression of the target are constructed by genetic engineering, using a range of cloning methods as well as total gene synthesis. Biotechnology then takes over for large-scale protein expression and purification

35 INFECTIOUS DISEASES AUTOIMMUNE DISEASES Upstream Setup work establishes successful production of the target proteins by host cells in the required amounts and with the required functionality. The main host cell systems for expression and production of recombinant proteins at DIARECT are baculovirus / insect cells and E. coli bacteria. These systems are available at differ ent culture volumes, with possible scale-up to up to bio - reactor / fermenter cultures. Since different expression systems have specific strengths and weaknesses, initial setup work establishes successful production of target proteins with the required functionality. Following successful upscaling, the process is transferred to the downstream applications. Downstream Harvesting, centrifugation, cell lysis and filtration are examples of important operations that precede the actual purification of the target protein and require state-of-the-art equipment. Chromatographic purification combines affinity separations based on engineered tag sequences with a variety of other separation methods. The final result is the custom protein, with the final formulation according to customer specifications. CUSTOM DESIGN

36 QUALITY MANAGEMENT DIARECT is one of the leading suppliers of antigens for autoimmune diagnostics. Focusing on our customers success, we are committed to having the highest level of quality in the field of assay components for diagnostic kits and biotech service. It is our aim to provide our customers with a level of quality and service that consistently meets and exceeds their expectations. Qualified employees are a prerequisite for the production of high-quality products like components of diagnostic assays. More than two-thirds of the DIARECT employees hold an academic degree in the fields of DNA technology, molecular biology, cell biology, protein chemistry or biotechnical engineering. Ongoing training programs maintain this high standard. Our employees embrace the quality management system and are active participants in our continuous improvement programs. Our laboratories were designed with quality in mind, and a full array of modern equipment enables us to maintain our high quality standards

37 INFECTIOUS DISEASES CUSTOM DESIGN AUTOIMMUNE DISEASES As our customers needs continue to change, we stand committed to permanent and continuous improvement. The products of DIARECT are therefore developed, produced, and distributed according to our Quality Management System that is certified for compliance with ISO 9001 as well as ISO standards. In addition, since September 2002 DIARECT has been listed as a manufacturer of human recombinant antigens for autoimmune testing in the database of the U.S. Food and Drug Administration (FDA). Production facilities of SurModics IVD, manufacturer of protein stabilizers / blockers and BioFX substrates and accessory reagents, distributed in Europe by DIARECT, operate in an environment in accordance to the ISO 9001 and ISO standards as well. In addition, the manufacturing sites of SurModics are regularly audited by DIARECT s quality representa - tives to guarantee distribution of products of highest quality

38 LOT-TO-LOT CONSISTENCY Lot-to-lot Consistency DIARECT recombinant antigens always pro d uced according to documented procedures (SOPs) undergo a rigorous series of tests in our quality control lab. Each lot is subjected to various biochemical and immunological analyses to assure conformance to our strict product specifications before it can be released. The goal of these extensive inspections is to ensure lot-to-lot conformance, which guarantees consistent results. The outstanding lot-to-lot consistency of our antigens reduces development times and efforts of our customers and increases their productivity. mod ITG Ab (lga): Comparison of 5 antigen lots Std. 1 Std. 2 Std. 3 Std. 4 Std. Std. 5 6 QC QC 1 2 Sample QC 3 QC 4 QC 5 QC 6 BD 1 BD

39 RESERVATION SYSTEM INFECTIOUS DISEASES AUTOIMMUNE DISEASES Reservation System We guarantee the reservation of a specified amount of antigen(s) (up to a whole production run) without any obligation. Usually the amount of antigen under reservation is sufficient for our customer s manufacturing needs for up to 18 months. You simply inform us of your antigen requirements for this period, and approximately every 4 months we will give you feedback regarding the accuracy of your estimate. The reservation system also includes providing the customer early enough with samples of new lots of the respective antigen. This allows for a smooth transition when evaluating for the qualification of a new lot for subsequent reservation. CUSTOM DESIGN For you there are two clear advantages: Security of supply with no additional costs No need for continual readjustment and fine tuning of your assay because of new antigen lots

40 ORDERING & SHIPPING Orders Orders may be placed by telephone, fax, and standard mail. Standing orders are welcome; for bulk prices please inquire. General Terms of Business: Our General Terms and Conditions of Sale and Purchase apply to all contracts concluded with DIARECT AG as well as to purchase orders, deliveries and services supplied by same (see Carrier & Payment Transportation: We are pleased to organize your dry ice shipment individually. Please contact us for options and more details. Payment: Terms of payment according to our General Terms and Conditions of Sale (see Contact Phone +49 (0)761 / Fax +49 (0)761 / orders@diarect.com

41 AUTOIMMUNE DISEASES Temperature profiles inside dry ice packages We have experimentally determined temperature profiles in dry ice packages packed according to our standard procedures. Result: We can guarantee that a package with 10 kg dry ice will retain a temperature below -20ºC for 5 days Result: We can guarantee that a package with 14 kg dry ice will retain a temperature below -20ºC for 6,5 days temperature temperature Temperature inside a package with 10 kg dry ice days Temperature inside a package with 14 kg dry ice outside temperature inside temperature outside temperature inside temperature INFECTIOUS DISEASES CUSTOM DESIGN days

42 INDEX Page AUTOIMMUNE DISEASES Alanyl-tRNA Synthetase (PL-12) 15 BCOADC-E2 (M2 component) 23 BPI (non recombinant) 19 Centromere Protein A (CENP-A) 13 Centromere Protein B (CENP-B) 13 Cytochrome P450 2D6 (LKM 1 hp) 21 DNA Topoisomerase I (Scl-70; full length) 13 DNA Topoisomerase I (Scl-70; non recombinant; bovine) 13 DNA Topoisomerase I (Scl-70; truncated) 13 dsdna (plasmid) 9 Formiminotransferase Cyclodeaminase (LC 1) 21 Gliadin (recombinant; deamidated) 17 Glomerular Basement Membrane (GBM; dissociated) 25 GP2 27 gp Histidyl-tRNA Synthetase (Jo-1) 15 Intrinsic Factor 27 Ku (p70/p80) 9 La/SS-B 11 M2 23 Mi-2 15 Myeloperoxidase (MPO; non recombinant) 19 Nucleolin 9 Nup62 23 OGDC-E2 (M2 component) 23 PDC-E2 (M2 component) 23 PM/Scl / 15 PM/Scl / 15 Proliferating Cell Nuclear Antigen (PCNA) 9 Proteinase 3 (PR3; non recombinant) 19 Ribosomal Phosphoprotein P0 9 Ribosomal Phosphoprotein P1 9 Ribosomal Phosphoprotein P2 9 RNP/Sm (non recombinant; bovine) 7 Ro/SS-A (52 kda) 11 Ro/SS-A (60 kda; non recombinant; bovine) 11 Ro/SS-A (60 kda; recombinant) 11 Sm (non recombinant; bovine) 7 Page SmD 7 SmD1 7 SmD2 7 SmD3 7 Sp SRP54 15 Threonyl-tRNA Synthetase (PL-7) 15 Thyroglobulin (non recombinant) 3 Thyroid Peroxidase (TPO) 3 Tissue Transglutaminase (ttg; expressed in Baculovirus/Sf9) 17 Tissue Transglutaminase (ttg; expressed in E. coli) 17 U-snRNP B/B 5 U1-snRNP 68/70 kda 5 U1-snRNP A 5 U1-snRNP C 5 β2-glycoprotein 1 (Apo H; non recombinant; bovine) 25 β2-glycoprotein 1 (Apo H; non recombinant; human) 25 β2-glycoprotein 1 (Apolipoprotein H) 25 INFECTIOUS DISEASES Borrelia afzelii BmpA 29 Borrelia afzelii DbpA 29 Borrelia afzelii (detergent extract) 29 Borrelia afzelii OspA 29 Borrelia burgdorferi BmpA 29 Borrelia burgdorferi DbpA 29 Borrelia burgdorferi DbpB 29 Borrelia burgdorferi (detergent extract) 29 Borrelia burgdorferi OspC 29 Borrelia burgdorferi p Borrelia burgdorferi p41 29 Borrelia garinii (detergent extract) 29 Borrelia garinii p58 29 Borrelia spielmanii OspC 29 Parvovirus B19 VLP VP1/VP2 Co-Capsid 31 Parvovirus B19 VLP VP

43 Page Lot-to-Lot Consistency 36 Ordering 38 Quality Management 34 Reservation System 37 Shipping 38 Temperature profiles inside dry ice packages 39 Pricelist available. Please inquire: For further information please visit Copyright: October 2011 AUTOIMMUNE DISEASES INFECTIOUS DISEASES CUSTOM DESIGN

44 The Quality League of Immunodiagnostic Components DIARECT AG Bötzinger Strasse 29 B Freiburg Germany Phone +49 (0)761 / Fax +49 (0)761 / orders@diarect.com