Date: Jun 25, 2015 Source: Company Data (
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In a first for the field, the academic labs of Stealth co-founders Bailey-Kellogg and Griswold have demonstrated direct connections all the way from deletion of T cell epitopes through reduction of anti-drug antibody titers to improvement of therapeutic efficacy. The researchers have been developing engineered variants of lysostaphin, a potent anti-staphylococcal enzyme (including against methicillin resistant strains, MRSA), whose clinical translation has been held back due in part to immunogenicity issues. In a recent Chemistry & Biology paper, the team used computationally-driven, structure-based protein design to achieve widespread deletion of lysostaphin's T cell epitopes. When administered to humanized HLA transgenic mice, the deimmunized lysostaphins exhibited greatly suppressed anti-drug antibody responses, and in turn the engineered variants were able to rescue mice from repeated MRSA challenges. This stands in contrast to wild-type lysostaphin, which elicited escalating anti-drug antibody titers upon repeated administration and as a result failed to protect humanized mice from recurrent MRSA challenges. As previously summarized, Dartmouth and Stealth Biologics have secured an NIH STTR grant to further advance the design and development of this next-generation antibiotic.
Press coverage of this breakthrough in biotherapeutic deimmunization includes articles in ACS noteworthy chemistry, Biocentury Innovations, and Chemical & Engineering News.
Stealth Biologics has developed proprietary design algorithms that enable widespread application of the principles demonstrated in engineering deimmunized lysostaphin. Our methods integrate computational assessments of immunogenicity and molecular function within a powerful global optimization framework. These tools enable rapid development of stable and highly active lead candidates that are depleted of immunogenic T cell epitope hotspots, the underlying drivers of anti-drug antibody responses that can undermine therapeutic efficacy.
