Possible new second-generation multiple sclerosis therapy

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Scientists from Genencor International, Inc., have demonstrated in an in vivo model that a new variant of recombinant interferon-beta reduces the immunological response to the protein. Administration of recombinant interferon-beta is the standard-of-care treatment for Relapsing Remitting Multiple Sclerosis (RRMS) patients, and the production of neutralizing antibodies against interferon-beta may reduce the effectiveness of this treatment in up to 30 percent of RRMS patients.

The Genencor data, published in the current issue of Journal of Immunology, extend studies published earlier this year (Genes and Immunity (5 (1), 1-7, 2004) by providing an in vivo test of the I-mune(R) method for creating reduced immunogenicity protein variants. Using Genencor's proprietary I-mune(R) assay and platform, the scientists generated a variant of interferon-beta by changing an amino acid at a single position in the immunodominant CD4+ T cell epitope region of the protein.

The immunodominant epitope in the parent protein had been shown in an earlier report published by Genencor scientists to be critical for immunologic responses in both humans and Balb/c mice. The scientists showed that T cells from mice immunized with the variant and challenged with the parent interferon-beta had significantly lower proliferation than has been seen following immunization with unmodified interferon-beta.

Further, the IgG antibody response to the variant interferon-beta molecule was almost completely absent. The data showed that the single amino acid change did not disrupt the overall structure of the interferon-beta protein as evidenced by no alterations in antibody-binding epitopes. Importantly, the resulting variant interferon-beta (known as I129V) was equally active as the original molecule in functional assays. "Our I-mune assay had identified both dominant and subdominant epitopes within interferon-beta.

The current findings suggest that modification of the immunodominant epitope eliminates the need to modify other subdominant ones, thus reducing work needed to create new generations of important protein drugs," said Mark A. Goldsmith, M.D., Ph.D. Genencor's senior vice president, Health Care. "We believe that our technology can be used to minimize immunogenicity problems that are frequently encountered in late-stages of protein drug development in the absence of immuno-optimization."


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