Ebola (EBOV) and Marburg (MARV) viruses cause hemorrhagic fever disease in humans and nonhuman primates (NHPs) with case-fatality rates as high as 90%. The 2013-2016 Ebola Virus Disease (EVD) outbreak led to over 28,000 cases and 11,000 deaths and took an enormous toll on the economy of West African nations, in the absence of any vaccine or therapeutic options. This outbreak spurred an unprecedented global effort for development of vaccines and therapeutics for EVD and led to an approved vaccine and two monoclonal antibody (mAb) therapeutics. Importantly studies with EBOV mAbs and later SARS-CoV2 mAbs established the value of mAb cocktails for effective treatment of viral diseases. In contrast to EVD, development of therapeutics for Marburg Virus Disease (MVD) has been lagging despite several MVD outbreaks including one in 2022. The investigators on this MPI Phase I/II Fast Track SBIR application have developed two classes of mAbs targeting non-overlapping epitopes within the receptor binding site (RBS) and the internal fusion loop (IFL) of MARV glycoprotein (GP). The RBS-binding mAb (MR186), provides protection primarily through effector functions, while the IFL-binder (R217) is the most potent neutralizing MARV mAb discovered to-date. MR186 has been engineered to enhance bioavailability using YTE mutation in the Fc portion, and produced in a fucosyl- transferase deficient CHO cell line to enhance effector functions (MR186-YTEAF). We are currently introducing YTE mutations into R217 Fc to generate the therapeutic candidate R217-YTE. In this proposed project we harness these complementary mechanisms of action to develop a highly effective cocktail of these two mAbs for MVD treatment. Use of mAb cocktail is also expected to reduce the risk of escape variant. The proposal has four Specific Aims. In Aim 1 (Phase I portion), R217-YTE will be produced in ExpiCHO cells and fully characterized. Superior efficacy of the cocktail will be demonstrated in a guinea pig model of MARV-Angola and this milestone will serve for transition to Phase II SBIR. Phase II Portion starts with Aim 2, in which the efficacy of the cocktail will be tested in NHP models in series of adaptively designed NHP experiments and finally the superior efficacy will be formally demonstrated in comparison with the individual mAbs. In Aim 3 we will evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of the antibodies in sera from a number of NHP efficacy studies including studies performed in Aim 1. Correlations between PK/PD data and clinical outcome will be explored. Aim 4 we will be focused on generation of stable manufacturing cell lines in CHO cells and at lease four clones of each mAb will be produced to be used for future GMP cell banks. If successful, we anticipate further development of the product under DoD or BARDA funding and approval under FDA Animal Rule.
Public Health Relevance Statement: Filoviruses are among the deadliest pathogens known to humans. The Ebola virus disease outbreak in West Africa (2014-2016), caused by the Zaire Ebola virus, resulted in over 28,000 cases and 11,000 deaths. In addition to Ebola virus, a related filovirus called Marburg has caused five outbreaks in the past 10 years with high fatality rates. This proposal is aimed at developing effective immunoprotherapeutic against Marburg virus for protection against Marburg virus disease. We have generated several antibody drug candidates that protect against Marburg infection. Under this proposal we will engineer two lead antibody to acquire long term durability after injection and we will perform animal efficacy studies with a cocktail of these antibodies. This study, if successful, will set the stage for clinical development of an effective therapeutic for human use.
Project Terms: Binding Determinants; Epitopes; Binding Sites; Combining Site; Reactive Site; Biological Availability; Bioavailability; Physiologic Availability; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Biological Response Modifier Therapy; Biological Therapy; biological therapeutic; biological treatment; biologically based therapeutics; biotherapeutics; biotherapy; Blood Chemical Analysis; Blood Chemical Analyses; blood chemistry; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Comparative Study; Complete Blood Count; Cessation of life; Death; Disease; Disorder; Disease Outbreaks; Outbreaks; Ebola virus; EBOV; Ebola-like Viruses; ebolavirus; Engineering; Exhibits; Fucosyltransferase; Alpha-Fucosyltransferases; Future; Glycoproteins; Viral Hemorrhagic Fevers; hemorrhagic fever; Human; Modern Man; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; Infection; Lead; Pb element; heavy metal Pb; heavy metal lead; Macaca fascicularis; Crab-Eating Macaque; Crab-Eating Monkey; Cynomolgus Monkey; Cynomolgus macaque; M fascicularis; M. fascicularis; Marburgvirus; Frankfurt-Marburg Syndrome Virus; Marburg; Marburg virus; Marburg-like Viruses; Marburg Virus Disease; Marburg hemorrhagic fever; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Drug Kinetics; Pharmacokinetics; Regression Analysis; Regression Analyses; Regression Diagnostics; Statistical Regression; Research; Research Personnel; Investigators; Researchers; Sampling Studies; Survival Analysis; Survival Analyses; Testing; Time; Transfection; Vaccines; Viremia; viraemia; viral sepsis; virusemia; Virus Diseases; Viral Diseases; viral infection; virus infection; virus-induced disease; Virus; Generations; Measures; CHO Cells; Chinese Hamster Ovary Cell; Guinea Pigs; Guinea Pigs Mammals; Cavia; bases; base; Surface; Clinical; Phase; Variation; Variant; Series; Filoviridae; Filovirus; Blood Serum; Serum; Individual; non-human primate; nonhuman primate; African; Funding; antibody based therapies; antibody treatment; antibody-based therapeutics; antibody-based treatment; Antibody Therapy; Collaborations; Case Fatality Rates; Ebola Virus Disease; Ebola disease; Ebola Hemorrhagic Fever; Therapeutic; neutralizing antibody; Viral; receptor binding; receptor bound; success; vaccine development; develop a vaccine; develop vaccines; development of a vaccine; stable cell line; Animal Model; Animal Models and Related Studies; model of animal; Disease Outcome; novel; sobriety; sober; Reporting; Pharmacodynamics; Modeling; Property; cell bank; Zaire Ebola virus; ZEBOV; Zaire ebolavirus; reduce risk; reduce risks; reduce that risk; reduce the risk; reduce these risks; reduces risk; reduces the risk; reducing risk; reducing the risk; risk-reducing; Risk Reduction; Molecular Interaction; Binding; Fatality rate; Dose; Aman; Data; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Monitor; Development; developmental; designing; design; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; Outcome; pathogen; neutralizing mAb; neutralizing monoclonal antibodies; MAb Therapeutics; monoclonal antibody drugs; therapeutic mAbs; Therapeutic Monoclonal Antibodies; prototype; therapeutic agent development; therapeutic development; FDA approved; effective treatment; effective therapy; product development; protective efficacy; animal rule; animal efficacy; drug candidate; GP2; Glycoprotein 2, Zymogen Granule Membrane; Zymogen Granule Membrane Glycoprotein 2; GP2 gene; GP1; GTP-Binding Protein 1; GTPBP1; GTPBP1 gene; experiment; experimental research; experiments; experimental study; efficacy study; clinical development; therapeutic candidate; antibody immunotherapy; Injections; secondary end point; secondary endpoint; primary end point; primary endpoint; PK/PD; pharmacokinetics and pharmacodynamics; 2019 novel corona virus; 2019 novel coronavirus; COVID-19 virus; COVID19 virus; CoV-2; CoV2; SARS corona virus 2; SARS-CO-V2; SARS-COVID-2; SARS-CoV-2; SARS-CoV2; SARS-associated corona virus 2; SARS-associated coronavirus 2; SARS-coronavirus-2; SARS-related corona virus 2; SARS-related coronavirus 2; SARSCoV2; Severe Acute Respiratory Coronavirus 2; Severe Acute Respiratory Distress Syndrome CoV 2; Severe Acute Respiratory Distress Syndrome Corona Virus 2; Severe Acute Respiratory Distress Syndrome Coronavirus 2; Severe Acute Respiratory Syndrome CoV 2; Severe Acute Respiratory Syndrome-associated coronavirus 2; Severe Acute Respiratory Syndrome-related coronavirus 2; Severe acute respiratory syndrome associated corona virus 2; Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome related corona virus 2; Wuhan coronavirus; coronavirus disease 2019 virus; coronavirus disease-19 virus; hCoV19; nCoV2; 2019-nCoV; Ebola; therapeutically effective; guinea pig model; viral outbreak; viral disease outbreak; virus disease outbreak; manufacture; Africa; Angola; Antibodies; Clinical Treatment Moab; mAbs; monoclonal Abs; Monoclonal Antibodies; Antigenic Determinants
