GP38-Targeting Monoclonal Antibodies Protect Adult Mice Against Lethal Crimean- …

Description (excerpt)

CROSS REFERENCE TO RELATED APPLICATIONS This application is a Divisional of U.S. application Ser. No. 17/418,357 filed on Jun. 25, 2021, which is a § 371 National Stage Application of PCT/US2020/012621 filed on Jan. 7, 2020, which claims the benefit of U.S. Provisional Application Ser. No. 62/789,576, filed Jan. 8, 2019, the contents of which are herein incorporated by reference in their entirety. STATEMENT AS TO RIGHTS OR INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support from the Medical Research Institute of Infectious Diseases, a subordinate organization of the United States Army Medical Research and Materiel Command. The United States government has certain rights in the invention. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY Pursuant to the EFS-Web legal framework and 37 C.F.R. § 1.821-825 (see M.P.E.P. § 2442.03(a)), an official copy of the sequence listing is submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file named “ARM-02US_XML_May_7_2025.xml” saved on May 7, 2025, and having a size of 13,321 bytes is filed concurrently with the specification. The sequence listing contained in this ASCII formatted document is part of the specification and is herein incorporated by reference in its entirety. BACKGROUND Crimean-Congo hemorrhagic fever virus (CCHFV) is an enveloped virus in the Nairoviridae family (for a review see (1-3) that is spread in nature by ticks, primarily those of the genus Hyalomma . CCHFV has a tripartite, negative-sense RNA genome consisting of small (S), medium (M) and large (L) segments. While the S segment encodes the nucleocapsid protein (N) and the L segment encodes the RNA-dependent RNA polymerase, the M segment encodes the two structural glycoproteins (G N and G C ) in addition to nonstructural glycoprotein products. CCHFV infects a large number of wild and domesticated mammalian species, including bovines and ovines, in addition to some avian species such as ostriches. Infections in these animals are predominantly asymptomatic, but can produce a prolonged (>5 days) viremia (4, 5). CCHFV infection in humans, caused through tick bites, exposure to infected animals, or nosocomial infections, can lead to an acute and potentially life-threatening disease termed Crimean-Congo hemorrhagic fever (CCHF) (2, 6, 7). Infection is characterized as a febrile illness with varying degrees of coagulopathy, liver injury, neurological manifestations, respiratory distress, lymphocytopenia and thrombocytopenia (3). The mortality rate ranges from 3-80% and this large range is theorized to depend on multiple factors including viral strain, route of exposure, speed of diagnosis, and access to emergency health care. There are currently no FDA approved drugs to treat CCHFV, although, there is conflicting evidence that ribavirin protects against lethal human disease (8, 9). Passive antibody protection has been used in humans to protect against several viral hemorrhagic fever viruses, including New World arenaviruses and filoviruses (10, 11). Antibody-based therapies comprised of human survivor plasma have been used to treat CCHFV infected humans since the mid-20 th century (12-14). Two products, CCHF-Bulin and CCHF-Venin, both produced from plasma of convalescence patients, have been used in Bulgaria (14). These products are delivered either intramuscularly or intravenously, respectively. While some evidence suggests that these products can protect against CCHFV, there are a limited number of people treated and no controls used to verify the results. Human convalescent serum was used in Dubai during a small nosocomial outbreak and the five patients receiving the product survived, but two other patients were left untreated and succumbed to disease. These data suggest antibody therapies can protect against lethality (13). However, other studies have indicated antibody offers little protective efficacy (12). In general, passive immunotherapy against CCHFV in humans has produced mixed results with some studies demonstrating protective efficacy and others suggesting it is not protective. A major issue is the lack of statistical evidence these therapeutic options are efficacious owing to the limited number of cases where patients were treated. Overall, use of convalescent plasma, serum, or purified antibodies has been essentially abandoned due to safety issues regarding human convalescent products and the poorly defined nature of the product. The CCHFV glycoproteins encoded by the M-segment are expressed as a precursor polyprotein that is proteolytically cleaved along the secretory pathway and eventually produces the two major glycoprotein components G N and G C , the latter of which is the only known target of neutralization (15-17). Prior to the production of the mature proteins, protease processing generates an intermediate molecule termed pre-G N and G C , then pre-G N is further processed by protease to generate a G N and other products such as GP38 that are secreted from cells and have