ChBE Seminar Series: Jennifer Maynard, UT Austin
Tuesday, November 21, 2017
2108, Chemical and Nuclear Engineering Building
Speaker: Jennifer Maynard, Associate Professor of Chemical Engineering, University of Texas, Austin
Title: Engineering Next Generation Therapeutics to Combat Infectious Diseases
Of the 56 therapeutic monoclonal antibody products currently marketed in the U.S., four now target infectious disease indications. An additional 40 recombinant antibodies are in clinical trials for infectious indications, with 29 in phase II or III trials. The evolution of antibiotic-resistant bacteria, the emergence of new pathogens, and a growing population of immunocompromised individuals means that in many cases antibodies are an increasingly attractive therapeutic option. Next-generation antibody formats, including antibody-drug conjugates and single-domain antibodies as well as antibody mixtures and bispecific antibodies provide access to novel therapeutic mechanisms and allow for targeting a wider range of epitopes.
This talk will provide an overview of recent advances in the field and highlight two related on-going projects in my lab. First, to address a resurgence in pertussis in high resource countries and continued high rates of morbidity and mortality in low resource countries, we have developed and antibody therapeutic neutralizing the toxin primarily responsible for symptoms. This antibody has been engineered for high affinity binding, reduced immunogenicity and extended serum half-life. We have also characterized its mechanism of action, using biochemical, structural and cellular assays. We have shown hu1B7 is protective against disease in mouse and adolescent baboon models of disease. Moreover, a single dose can prevent disease symptoms in a neonatal baboon model when administered five weeks before experimental challenge.
Second, pertussis remains a public health concern since the current vaccine confers short-term immunity and prevents the symptoms of disease but does not reduce infection or transmission rates. An improved vaccine would be a more cost-effective strategy to address this disease. The adenylate cyclase toxin (ACT) is the leading candidate for inclusion in future vaccines, yet there is surprisingly little data detailing the mechanisms by which ACT confers protection or its appropriateness for manufacturing and formulation as a part of a multi-component vaccine. We have engineered this protein for improved production and stability and have identified a panel of neutralizing and non-neutralizing antibodies to aid in further engineering efforts. We are currently using the original ACT and our engineered variant in mouse immunization experiments to dissect ACT’s role in protection. Notably, addition of our engineered protein to the current acellular vaccine results in 97% increased bacterial clearance during the early stages of disease, likely by protecting macrophages and neutrophils from toxin activites.