Symphogen

Genentech, Inc.: Collaboration pact with Genentech 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. ==Multiclonal antibodies==

Recombinant monoclonal antibody mixtures 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. Recombinant multi-clonal antibodies, or mixtures of mAbs, 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 antibody 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 protein 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 transfection • Cells where the antibody is most highly expressed are selected through fluorescent 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 drug, 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. 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: Cynomolgus monkeys were used in preclinical studies. 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. ==References==