International Team Led By Humabs Biomed Identifies Novel Therapeutic Antibody Candidates Isolated From Zika-Infected Patients

Published: Jul 15, 2016

Broad implications for new strategies to develop Zika virus diagnostics and treatments

Data published in Science*

Humabs BioMed SA, a Swiss antibody therapeutics company, today announced a publication in the renowned scientific journal Science describing an in-depth analysis of the human antibody and T cell immune response to the Zika virus infection with implications for diagnostics, vaccine and treatment development.* The article is the result of an international team led by Humabs.

Zika virus is a mosquito-borne flavivirus with homology to Dengue virus. After its introduction into Brazil in 2015, Zika virus has spread rapidly in Latin America and in February 2016, the World Health Organization (WHO) declared it a Public Health Emergency of International Concern. While the main route of Zika virus infection is through bites by mosquitos, the virus may also be spread sexually and vertically from mother to child during pregnancy. Most of the Zika virus infections are asymptomatic or cause only mild symptoms. However, Zika virus infection can lead to neurological complications, such as Guillain-Barré Syndrome in adults and, of even greater concern, congenital birth defects such as microcephaly and other defects in the developing fetus. As of today, there is no preventive vaccine or specific therapy available.

The study published in Science reports the first characterization of the human immune response to ZIKV infection, showing that most of the antibodies elicited by Zika virus infection cross-react with Dengue virus. These cross-reactive antibodies are poorly neutralizing, but can potently enhance Zika virus and Dengue virus infection in vitro. Antibody-dependent enhancement occurs through binding of the tail of antibodies to Fc receptors that are found on multiple cell types, including macrophages and placental endothelial cells. These receptors can internalize viral particles coated by antibodies leading to virus replication and spread in cells otherwise not targeted by the virus. Since placental Fc receptors transfer maternal antibodies to the developing fetus, maternal antibodies to Dengue virus may also possibly help Zika virus transmission across the placenta. The antibody-dependent enhancement phenomenon is well known in cases of secondary Dengue infections, representing a risk factor for the development of a more severe disease. Importantly, the study demonstrates that cross-reactive antibodies induced by Zika virus infection can lethally enhance infection by Dengue virus, suggesting that Zika virus infection in humans may predispose to more severe infections with Dengue virus. “In contrast to the broad cross-reactivity observed with antibodies, we found that the T cell responses is to a large extent Zika-specific, a finding that may mitigate the severity of Dengue infection in Zika immune individuals,” said Federica Sallusto, co-last author of the study and Director of the Center of Medical Immunology at the IRB.

The study also illustrates the use of antibodies specific for the Zika virus in a blockade-of-binding assay that might be used as a highly specific serological diagnostic tool in large cohort clinical and epidemiological studies to investigate the risk of Zika virus disease enhancement and the real incidence rate of Zika virus congenital infection in areas endemic for other flaviviruses.

A highly potent neutralizing antibody was identified and engineered into the “LALA” form to not bind Fc receptors and shown to inhibit the enhancement of Zika virus infection by plasma derived from either Zika virus or Dengue virus infected patients and to protect animals when given before and after animals were challenged lethally with Zika virus. This class of highly potent antibodies holds the promise of being developed in their LALA versions as therapeutics to both prevent congenital Zika virus infection in pregnant women at risk of contracting Zika virus infection by directly neutralizing Zika virus, and also to serve as potential inhibitors of disease enhancement and transplacental infection by pre-existing cross-reactive antibodies.

“It took only four months to functionally select, clone and characterize more than 100 anti-Zika virus antibodies from the initial screening of human B cells derived from four convalescent patients. The most potent antibody capable to neutralize Zika virus in a preclinical model is now being developed by Humabs as an effective anti-Zika virus therapy to prevent congenital infections. I believe that our discoveries will also have a significant impact on the development of novel diagnostic approaches,” said Davide Corti, CSO and Senior VP of Humabs.

“This study represents another example of the rapid pathway established at Humabs for the isolation of large numbers of anti-infective antibodies and for the discovery and development of the best in class antibodies as potential new therapies against emerging pathogens,” said Filippo Riva, CEO of Humabs.

The study is the result of an international collaboration between the Swiss Biotech company Humabs BioMed SA and the Institute for Research in Biomedicine (IRB), Università della Svizzera italiana (USI), together with the University of California, Berkeley (US), Public Health England, Porton Down (UK), the Policlinico San Matteo IRCCS, Pavia (IT), the Swiss Tropical and Public Health Institute, Basel (CH), and the Centre for Tropical Medicine, Ho Chi Minh City (VN). The study was partially funded by the Swiss National Science Foundation and the European Research Council, the US National Institutes of Health and the Italian Ministry of Health.

* “Specificity, cross-reactivity and function of antibodies elicited by Zika virus infection,” by K. Stettler; M. Beltramello; S. Bianchi; F. Vanzetta; A. Minola; S. Jaconi; E. Cameroni; D. Corti at Humabs BioMed SA in Bellinzona, Switzerland; D.A. Espinosa; E. Harris at University of California, Berkeley in Berkeley, CA; V. Graham; S. Dowall; B. Atkinson; R. Hewson at Public Health England in Salisbury, UK; A. Cassotta; F. Mele; M. Foglierini; M. Pedotti; L. Simonelli; L. Varani; A. Lanzavecchia; F. Sallusto at Università della Svizzera italiana in Bellinzona, Switzerland; A. Cassotta; A. Lanzavecchia at ETH Zurich in Zurich, Switzerland; E. Percivalle; F. Baldanti at Fondazione IRCCS Policlinico San Matteo in Pavia, Italy; C.P. Simmons at University of Oxford in Oxford, UK; C.P. Simmons at Center for Tropical Medicine in Ho Chi Minh City, Vietnam; C.P. Simmons at University of Melbourne in Melbourne, VIC, Australia; C.P. Simmons at Peter Doherty Institute in Melbourne, VIC, Australia; J. Blum at Swiss Tropical and Public Health Institute in Basel, Switzerland; J. Blum at University of Basel in Basel, Switzerland.

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