Recombinant Fully-Human Monoclonal Antibodies for Prophylaxis and Treatment of Chikungunya Virus Disease
M. Mandron1, J Rothblatt1, H. Watson1, C. Luxemburger1, P. Cortez1, X. Marniquet1, N. Haese2, R. Broeckel2, S. Neilson3, G. Sapparapu5, S. Sukupolvi4, J. Fox4, D. Streblow2, J.G. Julander3, M. Diamond4, J.E. Crowe5 Jr, C. Wells1, K. Carter1
1Sanofi, Cambridge, MA, Bridgewater, NJ, Marcy L'Etoile, France; 2 Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon; 3Institute for Antiviral Research, Utah State University, Logan, UT; 4Departments of Medicine, Molecular Microbiology, and Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri; 5 Departments of Pediatrics, Pathology, and Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee
Chikungunya virus (CHIKV) is a mosquito-borne virus that causes an acute febrile syndrome in humans associated with debilitating joint and muscle pain that can persist from months to years. Currently no approved vaccines or therapeutics are available to prevent or treat CHIKV infections.
Numerous investigations are in progress to develop a CHIKV vaccine, but Sanofi in collaboration with key partners (DARPA, NIAID) is leading an ambitious fast to clinic program to develop an alternative approach using immunotherapy to prevent and also to treat CHIKV disease.
In this context, Sanofi established a collaboration with Vanderbilt University and Washington University where investigators isolated B cell clones from a convalescent patient that produced highly potent neutralizing antibodies specific for the CHIKV E2 envelope protein‡. Recombinant versions of the most potent of these were generated to further test the hypothesis that highly potent recombinant neutralizing antibodies can reduce viral burden at sites of infection and thus mitigate disease.
The activity of our lead monoclonal antibodies (mAbs) has been demonstrated in preclinical animal models of CHIKV infection. In two murine models, anti-CHIKV mAbs were able to significantly reduce foot swelling and viral titers in joints in a dose-dependent manner. This effect on viral burden was also demonstrated in a non-human primate (NHP) model showing a rapid and potent activity on circulating virus.
Moreover, we were able to demonstrate in a murine model that anti-CHIKV mAbs were able to protect against CHIKV infection when mAbs were administered up to 28 days before CHIKV infection.
Our lead mAb is now progressing to clinical development and we are working closely with our partner to implement a clinical development plan in order to provide as fast as possible a new solution for patients.
‡S. Smith et al. 2015. Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus. Cell Host Microbe 18, 86-95.