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Jan 1, 2010 (Vol. 30, No. 1)

Innovating Protein-Expression Systems

As Companies Diversify Portfolios, Production Processes Need to Be Retooled

  • Soluble IgG Receptors

    “We’re investigating soluble Fc IgG receptors as a therapy for autoimmune diseases,” says Peter Sondermann, Ph.D., CSO at SuppreMol.

    Membrane-bound Fc receptors are expressed on virtually all cells of the immune system except T cells, and their interaction with immune complexes (antigens recognized by multiple IgGs) will activate pathways that result in their destruction. In autoimmune disorders this activation has negative and sometimes life-threatening consequences as the antigens represent essential host structures.

    “In autoimmune diseases such as serum lupus erythematosis or rheumatoid arthritis the immune system turns against its host, and if it wins the battle, the kidneys or joints are destroyed,” Dr. Sondermann says, “so completing the membrane receptors with soluble receptor would have the potential to break the vicious cycle of antibody production, destruction of the target structure, and further activation of the immune system.”

    To do this, the SuppreMol team cloned and expressed a truncated, soluble IgG receptor molecule (sFcγRIIb) in E. coli, and successfully tested its ability to counteract the effects of autoimmune diseases in various animal models.

    The first condition approached by SuppreMol is idiopathic thrombocytopenic purpura (ITP), which manifests itself by destroying platelets through the engulfing and digesting action of activated macrophages. When the platelet count falls below a certain level, extravasation of blood from the vessels into the surrounding tissues occurs with often fatal consequences. Because its indication is clear and straightforward, the condition is an appropriate target for the SuppreMol therapeutic protocol.

    According to Dr. Sondermann, the immunomodulatory soluble receptor for the Fc portion of the IgG molecule is expressed in inclusion bodies of the prokaryotic expression systems in extremely high quantities. To obtain the active form, the inclusion bodies are separated from the cells and the resulting partially pure protein can be refolded and purified to obtain high yields.

    The company has successfully conducted Phase I studies with volunteers, and is now proceeding to point-of-care studies in ITP patients. In addition, upscaling the production of a cloned, truncated receptor will allow larger clinical investigations, encompassing additional indications. For this reason, SuppreMol is currently improving the production process by adaptation of the fermentation protocol as well as the refolding and purification steps, in order to optimize yields and production costs.

    Up to this point the most successful biologicals have anticancer antibodies, but the picture is rapidly changing as a number of new treatments for infectious diseases, immune disfunction and neurological disorders move through clinical trials and toward the market place. 

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