In this grant application, we propose to further advance the development of a pan-dengue antibody for potential use in passive immunization and therapeutic strategies. Dengue is the most important world-wide mosquito-borne viral disease, with over half of the world's population at risk for infection. Dengue is caused by four genetically related but serologically distinct viruses termed DV-1 to DV-4 that are members of the flavivirus genus. Recent estimates suggest that over 390 million infections occur per year, of which 96 million manifest clinical diseases. The high morbidity associated with dengue virus infection leads to significant public health, social, and economic impact on populations and countries where DVs are endemic. Dengue has been described as an emerging disease, with an increasing number of cases, disease severity, and geographical spread of the disease. There are currently no specific agents for the prevention or treatment of dengue, and several vaccine candidates are in development for dengue though none that are approved. Given the global health impact and expanding nature of dengue as well as a lack of specific agents to prevent or treat the disease, a potent therapeutic that targets all DVs would provide significant benefit towards meeting the large unmet clinical need for dengue. To this end, we have engineered, through computational chemistry and structural informatics, the antibody 4E5A, which efficiently binds and potently neutralizes DV1-4 and confers significant in vivo activity. The antibody targets an epitope on domain III of the E protei that is highly accessible on the virion and that is constrained in its ability to mutate. Given the attributes of 4E5A, we propose to further characterize and develop the antibody to Phase I clinical trials. Our studies will be aimed at (1) examining the safety and activity of 4E5A through a series of mechanistic in vitro studies and safety and efficacy in animal models of dengue, and (2) utilizing our structure-based network and protein engineering approach to probe structure (epitope)-activity and to identify additional backup candidates. Overall, 4E5A and related molecules will be used to test the clinical hypothesis that reducing viral titer through administration of an antibody will (a) reduce symptoms and (b) lessen or eliminate hemorrhagic complications associated with disease progression.

Public Health Relevance

Dengue is the most important world-wide mosquito-borne viral disease, with over half of the world's population at risk for infection and more than 90 million clinical infections per year. Dengue is an emerging infectious disease with increased incidence and geographic spread, and the high morbidity associated with dengue virus infection leads to significant public health, social, and economic impact on populations and countries where the disease is endemic. In this grant application, we propose to advance the development of a pan-dengue antibody, 4E5A, towards Phase I clinical trials as a countermeasure to dengue, through further characterization of the in vitro and in vivo safety and efficacy of this antibody.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI111395-05
Application #
9533970
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Challberg, Mark D
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
Tharakaraman, Kannan; Watanabe, Satoru; Chan, Kuan Rong et al. (2018) Rational Engineering and Characterization of an mAb that Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope. Cell Host Microbe 23:618-627.e6
Wong, Yee Hwa; Kumar, Akshita; Liew, Chong Wai et al. (2018) Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513. Sci Rep 8:8449
Quinlan, Devin S; Raman, Rahul; Tharakaraman, Kannan et al. (2017) An inter-residue network model to identify mutational-constrained regions on the Ebola coat glycoprotein. Sci Rep 7:45886
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Robinson, Luke N; Tharakaraman, Kannan; Rowley, Kirk J et al. (2015) Structure-Guided Design of an Anti-dengue Antibody Directed to a Non-immunodominant Epitope. Cell 162:493-504
Tharakaraman, Kannan; Subramanian, Vidya; Viswanathan, Karthik et al. (2015) A broadly neutralizing human monoclonal antibody is effective against H7N9. Proc Natl Acad Sci U S A 112:10890-5
Tharakaraman, Kannan; Sasisekharan, Ram (2015) Influenza surveillance: 2014-2015 H1N1 ""swine""-derived influenza viruses from India. Cell Host Microbe 17:279-282