Biologics

Polyclonal antibodies: a new class of biopharmaceuticals

Danish biotech company Symphogen A/S is developing recombinant polyclonal antibodies as drug candidates, and has pioneered new technology for the production of these therapeutics, which it says have several advantages over monoclonal antibodies as biopharmaceuticals.

ymphogen was established with the aim of developing and bringing to market innovative human recombinant antibody therapeutics that mimic the natural diversity, affinity and specificity of the immune response to treat diseases caused by complex antigens. The company is pioneering the development of recombinant human polyclonal antibodies, termed symphobodies, which offer advantages over current immunoglobulin and monoclonal antibody therapies. By applying these new technologies, Symphogen is developing a product pipeline that targets diseases caused by complex antigens, including infectious diseases, cancer, transplant rejection and allergies. The company currently has two products in preclinical development and two in research, and its pipeline is based on a proprietary platform comprised of Symplex and Sympress technologies for the selection and production of symphobodies. The Symplex technology is used for human antibody drug lead discovery and selection from human blood cells, and the Sympress technology is for expression and manufacturing of recombinant polyclonal antibodies. Symplex is used for discovery of truly human recombinant antibodies directly from human antibody-producing plasma cells that have been isolated from the blood of immunised individuals. The resulting antibodies are expected to provide potent and safe drug leads. Symplex preserves the original pairing of the antibody variable-region segments. This is achieved by isolating individual B lymphocytes from naturally immune human donors before cloning and linking the antibody variable-region gene segments through Symplex PCR. As well as being potent, due to the reduced risk of cross-reactivity against normal tissues, Symplexderived antibodies are expected to provide drug leads with lower attrition rates as the projects progress through development. The manufacturing of target-specific fully human recombinant polyclonal antibodies, or symphobodies, is achieved using Symphogens proprietary mammalian expression platform, Sympress. Based on industry-standard Chinese Hamster Ovary (CHO) cell lines, the technology enables site-specific integration of antibody genes, ensuring consistent and reproducible manufacturing of recombinant polyclonal antibodies from benchtop to production scale. Symphogen was founded in 2000 and has raised a total of $53 million to date in equity capital through an international investor syndicate. The company is located in Copenhagen, Denmark and currently employs about 50 people.

MEET KIRSTEN DREJER OF SYMPHOGEN

Dr Kirsten Drejer has 20 years of experience in the pharmaceutical industry. Before joining Symphogen, she held several scientific and managerial positions in Novo Nordisk, including three years as project manager, one year as the Head of Diabetes Pharmacology, four years as Director of Diabetes Discovery, and three years as Corporate Facilitator. Her scientific experience includes research and development of drugs for the treatment of diabetes and she was instrumental in the Insulin Analogue and Nasal Insulin programmess of Novo Nordisk. Dr Drejer serves on the Board of Directors of Bioneer A/S and BioCentrum DTU and she is a member of the Committee on the Industrial PhD Fellowship Programme under ATV, the Danish Academy of Technical Sciences.

Immune system characteristics

The specific human immune response is an advanced defence system with two important characteristics, diversity and specificity. When the immune system identifies an antigen or 34 MARCH 2006

foreign microorganism, it produces millions of antibodies against it. Antibody therapeutics are being developed against a variety of diseases. Three generations of antibodies have been developed: immunoglobulins, monoclonal antibodies and polyclonal antibodies. Immunoglobulins have been in medical use for more than 100 years. Immounoglobulins (Ig) contain a diverse array of antibodies, and are classified as a polyclonal antibody therapy. They are currently manufactured using two methods: normal Ig, which is isolated from the blood of healthy donors; and hyperimmune Ig, which is isolated from newly vaccinated donors or donors recovering from relevant disease. Immunoglobulins: Unfortunately, Ig therapeutics are associated with several disadvantages. First, only a small percentage of the large number of antibodies in immunoglobulins will be specific to a particular disease. In addition, because new viruses are continually evolving, the ability to develop effective diagnostics for emerging viruses is challenged, and even screened plasma may carry the risk of disease transmission. Third, the supply of Ig, especially hyperimmune Ig, is limited due to the difficulty of collecting sufficient blood from donors with a high response against a specific antigen. Finally, the collection, testing and isolation of Ig from blood are expensive procedures. Monoclonal antibodies: In 1976, Kohler and Milstein invented a technology for producing monoclonal, or identical, antibodies, which offered several advantages as antibody therapeutics. Monoclonal antibodies (mAb) are pure, highly specific against a single antigen, and can be prepared in unlimited supply. However, they are only effective against diseases in which a simple antigen is the cause. They bind only to a single surface structure on an antigen, and therefore have limited effect in the treatment of disease caused by complex antigens, for example in www.sp2.uk.com

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Biologics Outsourcing
2006
4 & 5 May 2006, Palau de Congressos de Catalunya, Barcelona, Spain
Biologics Outsourcing features presentations on the major issues in biologics manufacturing, including:
Opportunities in the biomanufacturing marketplace The relationship between the CMO and the customer Recombinant production/expression technologies for biopharmaceuticals Ion exchange chromatography for monoclonal antibody purification New technology for drug delivery of biopharmaceuticals

Key Speakers include:

Professor Rolf Werner Corporate Director Biopharmaceuticals Boehringer Ingelheim Dr Stephen Taylor VP Biologics Avecia Biotechnology Dr Amarpreet Dhiman Industry Analyst Healthcare Frost & Sullivan Dr Tony Bradshaw Director bioProcessUK Alex Bollen Chief Executive Officer Henogen SA

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To view the full conference programme or register as a delegate go to www.biofine.uk.com and click on Biologics Outsouring Conference in the Event Menu on the left.

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MARCH 2006

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Biologics
many forms of cancer and infectious disease. They have therefore been primarily used in the treatment of cancers characterised by the presence of one simple antigen. But even here, if the antigen mutates during treatment, the mAb potency is greatly diminished and it is possible that they may even no longer offer a therapeutic effect. Recombinant polyclonal antibodies: Recombinant polyclonal antibodies, or symphobodies, are a fully human and diverse array of antibodies targeting a complex antigen. Thus they resemble the positive traits of hyperimmune immunoglobulins without the drawbacks of blood-borne infectious disease risk and disruptions of supply due to lack of available donors. With symphobodies, the risk of transmitting infections is non-existent. Like monoclonal antibodies, symphobodies are highly specific and 100 per cent pure, and therefore greatly reduce the risk of unwanted side-effects because the patient is not administered any irrelevant antibodies, says Dr Kirsten Drejer, co-founder and chief executive officer of Symphogen. In addition, symphobodies can be produced in unlimited amounts using industry-standard recombinant CHO cell culture techniques. Therefore, they are superior to hyperimmune immunoglobulins and can replace them as a therapeutic option. Symphobodies can compete with monoclonal antibodies when used in the treatment of diseases caused by complex antigens, for example bacteria, virus, fungi or cancer. Recombinant polyclonal antibodies are expected to be more effective against targets that are prone to antigenic drift through mutation, such as infectious agents and cancer cells. In addition, unlike monoclonal antibodies which are characterised by competition for binding to the same epitope, polyclonals are able to bind to multiple epitopes on complex antigens.

Danish company Symphogen A/S has developed novel technologies for the discovery and manufacture of polyclonal antibody therapeutics.

Technology advantages

Antibodies isolated from human donors using Symphogens Symplex technology are truly human because they have been selected from a human background. This gives an advantage over existing monoclonal antibody discovery technologies such as phage display, in which the antibody drug leads are selected from large artificial combinatorial antibody libraries, and hybridoma technology in which the antibody drug leads are derived from animals, says Drejer. Polyclonal antibodies are expected to be superior to monoclonal antibody therapies in neutralisation or elimination of complex target antigens or antigens characterised by antigenic drift, such as cancer cells, bacteria, viruses or allergens. As polyclonals are able to bind to multiple epitopes of a complex antigen, they are not hindered by competition for the same epitope like monoclonal antibodies. Symphobodies offer a safe, homogenous, and highly specific product available in unlimited supply using industry-standard CHO cells for expression in mammalian systems. This offers significant advantages over existing polyclonal antibody therapies, which are isolated and purified as immunoglobulins from human blood. Such preparations may carry inherited risks of disease and are in general subject to supply shortages depending on blood donation supply constraints, she says.

The manufacture of Sym001 has been scaled to 400 litres, and batch-to-batch consistency has been demonstrated. Sym001 is currently undergoing GMP manufacture to produce materials for clinical trials scheduled to start this year, says Drejer. Last August the company entered into a patent licence agreement with Cambridge Antibody Technology (CAT) in which Symphogen received a licence to use CATs antibody phage display patents for research purposes and to develop and commercialise a number of therapeutic and diagnostic antibody products. Symphogen has used this first product licence option to develop and commercialise its lead product Sym001. We are very pleased to have secured access to Cambridge Antibody Technologys validated phage display patent estate, says Drejer. Combined with our proprietary antibody technology, this strengthens our competitiveness in the antibody arena. This partnership with CAT further supports the clinical development and commercialisation of our lead product, Sym001, for the treatment of Idiopathic Thrombocytopenic Purpura and Hemolytic Disease of Newborns. Our strategy is to build a strong portfolio of therapeutic recombinant polyclonal antibodies through our internal efforts and in collaboration with partners. Symphogens success in manufacturing consistent batches of polyclonal antibodies for clinical trials has attracted new investment. In January of this year the company announced the initial closing of a $25 million Series D financing which it will use to carry out clinical trials of Sym001. The companys existing investors together with Takeda Research Investment, Inc (TRI), the investment arm of Japans largest pharmaceutical company, participated in this financing round. We are fortunate to have an exceptional group of international investors who have demonstrated their commitment to Symphogen, says Drejer. It is a significant achievement that our first product, consisting of 25 distinct antibodies, has now been produced according to GMP and in 2 sufficient amounts to commence Phase I/II clinical trials. sp

FURTHER INFORMATION
Kirsten Drejer Symphogen A/S Elektrovej Building 375 DK-2800 Lyngby Denmark Tel: +45 4526 5050 Fax: +45 4526 5060 Internet Links:

Reproducible scale-up of symphobodies

Symphogen has demonstrated proof-of-concept for the effective utilisation of the Symplex and Sympress discovery and manufacturing platforms for multiple products. The companys lead product, Sym001 (anti-Rhesus D), consists of 25 different anti-Rhesus D antibodies. The antibodies constituting the product have all been transfected into the CHO manufacturing cell line. Stable expression of functional anti-Rhesus D antibodies has been demonstrated for all antibodies. 36 MARCH 2006

Email: info@symphogen.com Web: www.symphogen.com www.sp2.uk.com

Life science discovery & development

BioFine 2006 : May 4 & 5, Barcelona

The 3rd BioFine event will take place in Barcelona on May 4 & 5 2006. BioFine continues to grow and will have 3 conference tracks this year targeting unique areas in the life science discovery and development pipeline. BioFine offers you:
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