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The Company

The Company. Founded in 2004 by: Graeme Radcliffe Newsdesk PRNewswire Kevin Slater LumiTech Cambrex. Personnel. Chief Executive - Kevin Slater Lab Manager - Ilias Alexandrakis Operations Manager - Renu Tuli. Objectives.

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The Company

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  1. The Company

  2. Founded in 2004 by: Graeme Radcliffe Newsdesk PRNewswire Kevin Slater LumiTech Cambrex

  3. Personnel Chief Executive - Kevin Slater Lab Manager - Ilias Alexandrakis Operations Manager - Renu Tuli

  4. Objectives • Address the problem of cancer in pets by providing veterinary diagnostic services based on the latest technology • Extend the technology platform to encompass other major animal diseases • Extend the information base to human health through collaboration

  5. There are 8-10.5 million dogs in the UK 39% of UK households own at least one dog. 3700 veterinary practices in the UK 78 million dogs in the USA (Greater than the human population of the UK) 25 % of dogs will die of cancer For dogs over 10 years of age, approximately 50% of deaths are cancer-related. The veterinary profession is demanding improvements to diagnostic testing, driven by advances in human medicine PetScreen has addressed these needs by developing the World’s first Canine Lymphoma Blood Test

  6. Introduction – Canine Lymphoma

  7. Serum Biomarkers • Serum easily accessible • Potential for picking up circulating biomarkers • Diverse array of cancers whereby potential biomarkers identified • Prostate cancer • Breast cancer • Melanoma • Developed a serum biomarker approach to assist with detection of canine lymphoma

  8. Canine Lymphoma - Incidence • 20% of all canine tumours are lymphoma cases • 0.1% of older dogs will develop lymphoma • Very high incidence in some breeds, e.g. Golden Retrievers Canine Lymphoma - Symptoms • Lymphadenopathy • Lethargy • Weakness • Fever • Anorexia • Depression • Pu/Pd

  9. Types of Lymphoma • Multicentric lymphoma - usually shows up first as painless but enlarged peripheral lymph nodes. Owners may see or feel these in areas under the jaw, in the armpits, in the groin area or behind the knees. Enlargement of the liver and/or spleen can also occur, causing the abdomen to distend. This is the most common form of lymphoid cancer in dogs. • Gastrointestinal (alimentary) lymphoma - is a malignant form of cancer that can show up anywhere along the gastrointestinal tract (stomach, small intestine, large intestine, rectum). Clinical signs of gastrointestinal lymphoma include vomiting, diarrhoea, weight loss, lethargy, depression, diarrhoea and melena. Low serum albumin levels and elevated blood calcium levels commonly accompany alimentary lymphoma, although these can only be detected by veterinary evaluation of blood samples. This is the second most frequent form of lymphoma in dogs. • Mediastinal lymphoma - where the cancer is localized to tissues in the chest cavity - can cause fluid to build up around the lungs. This can lead to coughing and laboured breathing (dyspnoea), mimicking the signs of congestive heart failure. • Lymphoma of the skin (cutaneous lymphoma) - is uncommon in dogs. When it does occur, it usually shows up with hair loss (alopecia) and visible bumps on the skin. It can also be itchy (pruritic) and vary widely in appearance, ranging from a single lump to large areas of bruised, ulcerated and/or hairless skin. • Lymphoma of the central nervous system (CNS) - is very uncommon in dogs. When lymphoma is localized in the CNS, dogs typically present with neurological signs such as circling, seizures, behaviour changes and incoordination

  10. Canine Lymphoma – Diagnosis • Cytology • Histology • Immunophenotyping (T or B cell) Canine Lymphoma – Cost

  11. Canine Lymphoma – Treatment • Surgery • Chemotherapy • Radiation Therapy • Canine Lymphoma – Prognosis • B-cell lymphoma favorable to T-cell lymphoma • Clinical stage (Stage V has poorer prognosis against Stage I) • Dogs treated with chemotherapy experience a greater survival time

  12. Directed Chemotherapy Assay (DCA) Tumour Biopsy Dissect in 1 mm3 fragments Enzyme dissociation 6 days incubation time and the cell viability is determined by the quantification of the ATP levels using a luminometer. Cells dispension to microplate and application of 8 different chemotherapeutical drugs Individual cells

  13. Requirements for the Proteomic Test Sample collection must be simple and robust for veterinary use. Test performed on serum samples. 2 ml venous blood taken into gel tube • Coagulate for 30 minutes at room temperature • Centrifuge to remove blood cells • Ship sample for MS analysis Originally developed a test based on frozen sample, but this would not facilitate large scale up take, therefore redesigned it for chill shipped samples Knew this would lose biomarkers, but needed a practical test.

  14. MW 7.5 5 2.5 0 2000 4000 6000 8000 LBT - Proteomic Analysis + - + + - - - - - - - + + - - - - + + + + Serum Fractionation CM10 arrays SELDI-TOF MS

  15. LBT – Protein Identification

  16. Acute Phase Protein Response in Dogs Infection Inflammation Monocyte - Macrophage IL-1 TNF-α IL-6 C-RP Haptoglobin SAA AGP Liver

  17. Canine Lymphoma Blood Test Development Development of a multi marker test using Acute Phase Proteins (Haptoglobin, CRP) Use of Biomarker Pattern Software to create unique algorithms More than 12 protein peaks identified as significantly different on MS Further investigation in order to characterise and identify the proteins Identification of Haptoglobin A unique new method of quickly and accurately diagnosing canine lymphoma . The combination of two Acute Phase Protein Assays, Haptoglobin and a specific canine CRP, combined with a unique Diagnostic Algorithm provide a diagnostic system

  18. Method • Serum samples collected from dogs with lymphoma, healthy dogs and dogs with other diseases (many with similar presentation to lymphoma). Positive samples were confirmed by either FNA or excisional biopsy. Non lymphoma dogs were confirmed to be free of the disease at a minimum of six months after providing the serum sample • Samples were tested in batches • Samples stored at -20oC until tested • Ciphergen Biomarker Pattern Software was used to generate a series of algorithms using the Classification and Regression Tree (CART) procedure. Through an iterative process, the software uses the training set of data to build trees to a point when optimal differentiation between the populations is achieved. • Blinded sample test performed.

  19. Group Breakdown Condition of Dog Number in Group Lymphoma 64 Healthy 51 Other Diseases 79 Staging

  20. Results

  21. CRP Solid phase sandwich ELISA Haptoglobin Functional Colorometric Assay

  22. Clinical Utility of CLBT • Add-on test for the routine diagnosis of lymphoma • Remission monitoring • Screening population • Reflex testing as a follow on test for hypercalcaemia – Antech perform 10,000 biochemistry tests per day, of which 570 are hypercalcaemic.

  23. Remission Monitoring

  24. CRP levels taken at pre-treatment, midpoint remission, pre-relapse and relapse • n = 15 dogs

  25. Breakdown of the timescale for increase in CRP levels prior to relapse n = 15 dogs B A

  26. Comparison of CRP and Hapt levels in confirmed lymphoma patients when either treated with steroids or free of the drug n = 17 dogs n = 21 dogs

  27. Project with the University of Leicester • Further development of the existing test • Data mining with novel statistical tools • Data visualization with innovative technologies

  28. Project Deliverables Development of an Applet for the differential diagnosis of lymphoma and benign lymphoid hyperplasia. Adaptable Ability to evolve User friendly

  29. Project Benefits

  30. Advantages • A simple blood test • Can be used as part of blood work up at initial appointment • Complete test takes approximately one hour • Results available same day • Similar cost to FNA but less invasive • Early diagnostic • No anaesthetic required

  31. Summary • MS and other proteomic work confirmed already known findings that APP levels are increased in canine lymphoma • Application of CART algorithms is able to confer improved specificity over previously non-specific APP assays. • The Applet developed with the University of Leicester uses a unique algorithm taking into account the levels of C-Reactive Protein, Haptoglobin, age, sex and lymphadenopathy status of the patient. • The CLBT now provides a % risk probability of lymphoma.

  32. Further Development Feline Lymphoma IBD • Proteomic profiles were compared from 20 pre-treated cats diagnosed with lymphoma and 20 control samples (both healthy and diseased). • 6 peaks were identified which were significantly different between the 2 groups at the p<0.05 level. • CART (Classification and Regression Tree) analysis was performed on these data.

  33. Questions ???

  34. Comparative Research From 2 Legs to 4 and Back Again

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