Symphogen
Encyclopedia
Symphogen is a biotechnology company located in Copenhagen
, Denmark
that produces recombinant polyclonal antibody
drugs for disease treatment and prevention. Their three main areas of therapeutic research are immunoglobulin replacement, cancer, and infectious diseases. The company was founded in 2000 and has patents on a drug discovery platform called Symplex and a drug manufacturing platform called Sympress. Currently, ten drugs are being developed with rozrolimupab
(Sym001) being the lead product.
which enables both companies to utilize Symplex technology to help discover new antibodies against three undisclosed infectious disease targets.
Meiji Seika Kaisha, Ltd: Sym006 development and license agreement with Meiji Seika
that establishes a collaboration of research, development, and commercialization.
Biovitrum: A co-development and commercialization agreement with Biovitrum
for Sym001. The United States Food and Drug Administration granted an orphan drug designation to Sym001.
NIAID/NIH: Sym002 developmental grant with the National Institutes of Health
for a recombinant polyclonal antibody against smallpox. The grant enables Symphogen to complete pre-clinical development of Sym002, which allows submission of an Investigational New Drug application for new safety studies.
Symphogen claims that their proprietary polyclonal antibodies reflect both the diversity of immunoglobulins and specificity of monoclonal antibodies. It is possible to produce an unlimited supply of these antibodies using traditional large-scale biological manufacturing techniques, and it is claimed that these antibodies are produced with no risk of viral or prion transmission. This new class of therapeutic antibodies could be effective in treating complex diseases such as cancer for it allows the combination of several treatment modalities in one drug.
Recombinant polyclonal antibodies could be advantageous for the following reasons:
Symplex Process:
Sympress Technology is the manufacturing platform used to produce recombinant polyclonal antibodies in high yields. This technology enables the production of consistent mixtures of polyclonal antibodies with high batch-to-batch consistency at an industrial scale.
Sympress Process:
Sympress I Technology has been used to develop the product Sym001. Recently, Sympress II Technology has been developed, and it uses random gene integration to improve the expression yield.
, is a recombinant polyclonal antibody consisting of twenty-five monoclonal antibodies that is being developed for treatment of various hematological diseases such as, Idiopathic Thrombocytopenic Purpura
and Hemolytic disease of the newborn
.
Sym004 is a combination of two chimeric monoclonal antibodies
(mAB), 992 and 1024, developed using the mSymplex process that inhibits tumor growth in a number of cancerous cell lines including A431NS (A431 cells
). When used together, 992 and 1024 cross link epidermal growth factor receptor
(EGFR) and the EGFR is rapidly internalized and undergoes degradation. Alone, these mAbs are unable to effectively induce degradation of EGFR and inhibit tumor growth. mAb 992 and 1024 are thought to work synergistically. The antibodies bind to different epitopes on the receptor and their cooperation shows a statistically significant improvement on tumor growth inhibition over non-synergistic use of the antibodies . Alone, Sym004 has been shown to be more potent than Cetuximab
, a monoclonal antibody used to block ligands from accessing the EGFR, because Sym004 induces removal of the receptor from the cell surface. Sym004 also inhibits tumor cell growth because removal of the EGFR prevents it from cooperating with other receptors and signaling molecules in the tumor cell .
Clinical Results:
Dose range finding studies showed an increase in cynomolgus monkey kidney weight and decrease in body weight in respect to the control group, but both effects were reversible. The clearance of Sym004 is dependent on antibody mediated receptor internalization . Due to the efficiency of Sym004 induction of receptor internalization, repeat dose studies showed little accumulation of Sym004 and the clearance
rate was higher than Cetuximab. Because EGFR is expressed in the skin and gastrointestinal tract, the only toxic side effects observed were rash and diarrhea, and presented much earlier than Cetuximab.
Current Status:
Phase I trials finished in June 2011 in patients with colorectal cancer
and squamous cell carcinoma of the head and neck. Phase II trials are ongoing (24 weeks), beginning at Antwerp University Hospital in Belgium. Patients are receiving weekly doses, and the drug is being evaluated on “safety, efficacy, and pharmacokinetics of Sym004” .
Copenhagen
Copenhagen is the capital and largest city of Denmark, with an urban population of 1,199,224 and a metropolitan population of 1,930,260 . With the completion of the transnational Øresund Bridge in 2000, Copenhagen has become the centre of the increasingly integrating Øresund Region...
, Denmark
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
that produces recombinant polyclonal antibody
Polyclonal antibody
Polyclonal antibodies are antibodies that are obtained from different B cell resources. They are a combination of immunoglobulin molecules secreted against a specific antigen, each identifying a different epitope.- Production :...
drugs for disease treatment and prevention. Their three main areas of therapeutic research are immunoglobulin replacement, cancer, and infectious diseases. The company was founded in 2000 and has patents on a drug discovery platform called Symplex and a drug manufacturing platform called Sympress. Currently, ten drugs are being developed with rozrolimupab
Rozrolimupab
Rozrolimupab is a polyclonal antibody used in the treatment of autoimmune thrombocytopenic purpura, prevention of isoimmunization in Rh-negative pregnant women.This drug was developed by Symphogen A/S....
(Sym001) being the lead product.
Partner Collaborations
Genentech, Inc.: Collaboration pact with GenentechGenentech
Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
which enables both companies to utilize Symplex technology to help discover new antibodies against three undisclosed infectious disease targets.
Meiji Seika Kaisha, Ltd: Sym006 development and license agreement with Meiji Seika
Meiji Seika
is the trade name of a pharmaceutical company in Japan, , until March 31, 2011.It was the confectionery and pharmaceutical company that manufactures a wide range of products including Hello Panda and Yan Yan...
that establishes a collaboration of research, development, and commercialization.
Biovitrum: A co-development and commercialization agreement with Biovitrum
Biovitrum
Swedish Orphan Biovitrum is a Swedish pharmaceutical company, based in Stockholm, Sweden, with a product portfolio consisting of some 60 orphan and specialty pharmaceuticals.- History :...
for Sym001. The United States Food and Drug Administration granted an orphan drug designation to Sym001.
NIAID/NIH: Sym002 developmental grant with the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
for a recombinant polyclonal antibody against smallpox. The grant enables Symphogen to complete pre-clinical development of Sym002, which allows submission of an Investigational New Drug application for new safety studies.
Polyclonal Antibodies
Recombinant polyclonal antibodies mimic the diversity, specificity and binding capability of the natural immune system and increase the likelihood of the rapid elimination of the desired antigens. IgG antibodies are typically used due to their effectiveness in binding to many kinds of pathogens as well as protecting the body against the pathogens by immobilization, complement activation, opsonization for phagocytosis and neutralization of their toxins.Symphogen claims that their proprietary polyclonal antibodies reflect both the diversity of immunoglobulins and specificity of monoclonal antibodies. It is possible to produce an unlimited supply of these antibodies using traditional large-scale biological manufacturing techniques, and it is claimed that these antibodies are produced with no risk of viral or prion transmission. This new class of therapeutic antibodies could be effective in treating complex diseases such as cancer for it allows the combination of several treatment modalities in one drug.
Recombinant polyclonal antibodies could be advantageous for the following reasons:
- less sensitive to target diversification such as viral escape mutants
- hit multiple targets simultaneously
- create large immune complexes that activate effector functions
- create a higher density of antibodies on target surfaces enhancing downstream effector functions such as complement lysis, phagocytosis and antibody-dependent cell-mediated cytotoxicity
Symplex Technology
Symplex Technology is a process used to discover antibodies that are customized from plasma cells for a particular therapeutic application, and it involves direct isolation of the antibody genes from the immune system.Symplex Process:
- Immune cells are isolated from the spleen of mice or purified from human blood
- B-lymphocytes are separated using differences in cell densities
- Cells are individually sorted and antibodies are isolated
- Symplex PCR uses reverse transcription
- Heavy and light chains are amplified and conservatively paired back together in natural configuration
- Each antibodyAntibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
is cloned, placed into a bacterial vector and stored in a library - Antibodies are placed into a well (repertoire arraying) and the DNA is extracted and prepared
- DNA is transected to make proteinProteinProteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
and antibodies are cloned - The cloned antibodies are placed into wells and specifically chosen for further development based on antibody expression
- Antibody of choice from the original gene pairs (conjugate pairs) is chosen by screening
- A fully human antigen-specific antibody is produced
Sympress Technology
Sympress Technology is the manufacturing platform used to produce recombinant polyclonal antibodies in high yields. This technology enables the production of consistent mixtures of polyclonal antibodies with high batch-to-batch consistency at an industrial scale.
Sympress Process:
- Antibodies are encoded on plasmids using Chinese hamster ovary cell lines
- Cells undergo transfectionTransfectionTransfection is the process of deliberately introducing nucleic acids into cells. The term is used notably for non-viral methods in eukaryotic cells...
- Cells where the antibody is most highly expressed are selected through florescent tagging
- Cell lines are preserved and stored in cell banks
- The individual cell lines encoding the highest quality antibodies are mixed and produced in high yields
Sympress I Technology has been used to develop the product Sym001. Recently, Sympress II Technology has been developed, and it uses random gene integration to improve the expression yield.
Major Products
Of the ten products that Symphogen is in the process of developing, two have completed pre-clinical phases and have entered clinical trials. Both Sym001 and Sym004 are in Phase 2 clinical trials.Sym001
Rozrolimupab (Sym001), an orphan drugOrphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
, is a recombinant polyclonal antibody consisting of twenty-five monoclonal antibodies that is being developed for treatment of various hematological diseases such as, Idiopathic Thrombocytopenic Purpura
Idiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura is the condition of having an abnormally low platelet count of no known cause . As most incidents of ITP appear to be related to the production of antibodies against platelets, immune thrombocytopenic purpura or immune thrombocytopenia are terms also used to...
and Hemolytic disease of the newborn
Hemolytic disease of the newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta...
.
Sym004
Mechanism:Sym004 is a combination of two chimeric monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
(mAB), 992 and 1024, developed using the mSymplex process that inhibits tumor growth in a number of cancerous cell lines including A431NS (A431 cells
A431 cells
A431 cells are a model cell line used in biomedical research. More specifically, they are used in studies of the cell cycle and cancer-associated cell signalling pathways since they express abnormally high levels of the Epidermal growth factor receptor . As such they are often used as a positive...
). When used together, 992 and 1024 cross link epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR) and the EGFR is rapidly internalized and undergoes degradation. Alone, these mAbs are unable to effectively induce degradation of EGFR and inhibit tumor growth. mAb 992 and 1024 are thought to work synergistically. The antibodies bind to different epitopes on the receptor and their cooperation shows a statistically significant improvement on tumor growth inhibition over non-synergistic use of the antibodies . Alone, Sym004 has been shown to be more potent than Cetuximab
Cetuximab
Cetuximab is a chimeric monoclonal antibody, an epidermal growth factor receptor inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.- Distribution :Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers...
, a monoclonal antibody used to block ligands from accessing the EGFR, because Sym004 induces removal of the receptor from the cell surface. Sym004 also inhibits tumor cell growth because removal of the EGFR prevents it from cooperating with other receptors and signaling molecules in the tumor cell .
Clinical Results:
Dose range finding studies showed an increase in cynomolgus monkey kidney weight and decrease in body weight in respect to the control group, but both effects were reversible. The clearance of Sym004 is dependent on antibody mediated receptor internalization . Due to the efficiency of Sym004 induction of receptor internalization, repeat dose studies showed little accumulation of Sym004 and the clearance
Clearance
A clearance can refer to:* in chess, A positional move, where a player moves a piece occupying a certain square away, replacing it with an allied piece that will strengthen the player's position....
rate was higher than Cetuximab. Because EGFR is expressed in the skin and gastrointestinal tract, the only toxic side effects observed were rash and diarrhea, and presented much earlier than Cetuximab.
Current Status:
Phase I trials finished in June 2011 in patients with colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
and squamous cell carcinoma of the head and neck. Phase II trials are ongoing (24 weeks), beginning at Antwerp University Hospital in Belgium. Patients are receiving weekly doses, and the drug is being evaluated on “safety, efficacy, and pharmacokinetics of Sym004” .