PMID- 26468532 OWN - NLM STAT- MEDLINE DCOM- 20160426 LR - 20181113 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 90 IP - 1 DP - 2016 Jan 1 TI - Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein. PG - 279-91 LID - 10.1128/JVI.02172-15 [doi] AB - Filoviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. Current immunotherapeutic options for filoviruses are mostly specific to Ebola virus (EBOV), although other members of Filoviridae such as Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have also caused sizeable human outbreaks. Here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (MAbs) derived from cynomolgus macaques immunized repeatedly with a mixture of engineered glycoproteins (GPs) and virus-like particles (VLPs) for three different filovirus species. The antibodies recognize novel neutralizing and nonneutralizing epitopes on the filovirus glycoprotein, including conserved conformational epitopes within the core regions of the GP1 subunit and a novel linear epitope within the glycan cap. We further report the first filovirus antibody binding to a highly conserved epitope within the fusion loop of ebolavirus and marburgvirus species. One of the antibodies binding to the core GP1 region of all ebolavirus species and with lower affinity to MARV GP cross neutralized both SUDV and EBOV, the most divergent ebolavirus species. In a mouse model of EBOV infection, this antibody provided 100% protection when administered in two doses and partial, but significant, protection when given once at the peak of viremia 3 days postinfection. Furthermore, we describe novel cocktails of antibodies with enhanced protective efficacy compared to individual MAbs. In summary, the present work describes multiple novel, cross-reactive filovirus epitopes and innovative combination concepts that challenge the current therapeutic models. IMPORTANCE: Filoviruses are among the most deadly human pathogens. The 2014-2015 outbreak of Ebola virus disease (EVD) led to more than 27,000 cases and 11,000 fatalities. While there are five species of Ebolavirus and several strains of marburgvirus, the current immunotherapeutics primarily target Ebola virus. Since the nature of future outbreaks cannot be predicted, there is an urgent need for therapeutics with broad protective efficacy against multiple filoviruses. Here we describe a set of monoclonal antibodies cross-reactive with multiple filovirus species. These antibodies target novel conserved epitopes within the envelope glycoprotein and exhibit protective efficacy in mice. We further present novel concepts for combination of cross-reactive antibodies against multiple epitopes that show enhanced efficacy compared to monotherapy and provide complete protection in mice. These findings set the stage for further evaluation of these antibodies in nonhuman primates and development of effective pan-filovirus immunotherapeutics for use in future outbreaks. CI - Copyright (c) 2015, American Society for Microbiology. All Rights Reserved. FAU - Keck, Zhen-Yong AU - Keck ZY AD - Department of Pathology, Stanford University, Stanford, California, USA. FAU - Enterlein, Sven G AU - Enterlein SG AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA. FAU - Howell, Katie A AU - Howell KA AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA. FAU - Vu, Hong AU - Vu H AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA. FAU - Shulenin, Sergey AU - Shulenin S AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA. FAU - Warfield, Kelly L AU - Warfield KL AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA. FAU - Froude, Jeffrey W AU - Froude JW AD - U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA. FAU - Araghi, Nazli AU - Araghi N AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA. FAU - Douglas, Robin AU - Douglas R AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA. FAU - Biggins, Julia AU - Biggins J AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA. FAU - Lear-Rooney, Calli M AU - Lear-Rooney CM AD - U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA. FAU - Wirchnianski, Ariel S AU - Wirchnianski AS AD - U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA. FAU - Lau, Patrick AU - Lau P AD - Department of Pathology, Stanford University, Stanford, California, USA. FAU - Wang, Yong AU - Wang Y AD - Department of Pathology, Stanford University, Stanford, California, USA. FAU - Herbert, Andrew S AU - Herbert AS AD - U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA. FAU - Dye, John M AU - Dye JM AD - U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA. FAU - Glass, Pamela J AU - Glass PJ AD - U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA. FAU - Holtsberg, Frederick W AU - Holtsberg FW AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA. FAU - Foung, Steven K H AU - Foung SK AD - Department of Pathology, Stanford University, Stanford, California, USA. FAU - Aman, M Javad AU - Aman MJ AD - Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA javad@integratedbiotherapeutics.com. LA - eng SI - PDB/3CSY GR - R43 AI098178/AI/NIAID NIH HHS/United States GR - R43AI098178/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151014 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Neutralizing) RN - 0 (Antibodies, Viral) RN - 0 (Epitopes) RN - 0 (Glycoproteins) RN - 0 (Viral Proteins) SB - IM MH - Animals MH - Antibodies, Monoclonal/*immunology/isolation & purification/therapeutic use MH - Antibodies, Neutralizing/immunology/isolation & purification/therapeutic use MH - Antibodies, Viral/*immunology/isolation & purification/therapeutic use MH - Cross Reactions MH - Disease Models, Animal MH - Epitopes/*immunology MH - Female MH - Filoviridae/*immunology MH - Glycoproteins/*immunology MH - Hemorrhagic Fever, Ebola/*prevention & control MH - Immunization, Passive MH - Macaca MH - Mice, Inbred BALB C MH - Survival Analysis MH - Treatment Outcome MH - Viral Proteins/*immunology PMC - PMC4702572 EDAT- 2015/10/16 06:00 MHDA- 2016/04/27 06:00 PMCR- 2016/06/17 CRDT- 2015/10/16 06:00 PHST- 2015/08/26 00:00 [received] PHST- 2015/10/05 00:00 [accepted] PHST- 2015/10/16 06:00 [entrez] PHST- 2015/10/16 06:00 [pubmed] PHST- 2016/04/27 06:00 [medline] PHST- 2016/06/17 00:00 [pmc-release] AID - JVI.02172-15 [pii] AID - 02172-15 [pii] AID - 10.1128/JVI.02172-15 [doi] PST - epublish SO - J Virol. 2015 Oct 14;90(1):279-91. doi: 10.1128/JVI.02172-15. Print 2016 Jan 1.