A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses.
There is an urgent need for monoclonal antibody (mAb) therapies that broadly protect against Ebola virus and other filoviruses. The conserved, essential interaction between the filovirus glycoprotein, GP, and its entry receptor Niemann-Pick C1 (NPC1) provides an attractive target for such mAbs but is shielded by multiple mechanisms, including physical sequestration in late endosomes. Here, we describe a bispecific-antibody strategy to target this interaction, in which mAbs specific for NPC1 or the GP receptor-binding site are coupled to a mAb against a conserved, surface-exposed GP epitope. Bispecific antibodies, but not parent mAbs, neutralized all known ebolaviruses by coopting viral particles themselves for endosomal delivery and conferred postexposure protection against multiple ebolaviruses in mice. Such "Trojan horse" bispecific antibodies have potential as broad antifilovirus immunotherapeutics.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Anna Z
AZ
Wec
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Elisabeth K
EK
Nyakatura
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
Andrew S
AS
Herbert
Integrated Biotherapeutics Inc., Gaithersburg, MD 20878, USA.
Katie A
KA
Howell
Integrated Biotherapeutics Inc., Gaithersburg, MD 20878, USA.
Frederick W
FW
Holtsberg
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
Russell R
RR
Bakken
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Eva
E
Mittler
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
John R
JR
Christin
Integrated Biotherapeutics Inc., Gaithersburg, MD 20878, USA.
Sergey
S
Shulenin
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Rohit K
RK
Jangra
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Sushma
S
Bharrhan
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
Ana I
AI
Kuehne
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 10550, USA.
Zachary A
ZA
Bornholdt
Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN 37235, USA.
Andrew I
AI
Flyak
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 10550, USA.|The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 10550, USA.
Erica Ollmann
EO
Saphire
Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN 37235, USA. kartik.chandran@einstein.yu.edu jon.lai@einstein.yu.edu john.m.dye1.civ@mail.mil javad@integratedbiotherapeutics.com james.crowe@vanderbilt.edu.|Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA.|Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN 37232, USA.
James E
JE
Crowe
Integrated Biotherapeutics Inc., Gaithersburg, MD 20878, USA. kartik.chandran@einstein.yu.edu jon.lai@einstein.yu.edu john.m.dye1.civ@mail.mil javad@integratedbiotherapeutics.com james.crowe@vanderbilt.edu.
M Javad
MJ
Aman
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. kartik.chandran@einstein.yu.edu jon.lai@einstein.yu.edu john.m.dye1.civ@mail.mil javad@integratedbiotherapeutics.com james.crowe@vanderbilt.edu.
John M
JM
Dye
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA. kartik.chandran@einstein.yu.edu jon.lai@einstein.yu.edu john.m.dye1.civ@mail.mil javad@integratedbiotherapeutics.com james.crowe@vanderbilt.edu.
Jonathan R
JR
Lai
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. kartik.chandran@einstein.yu.edu jon.lai@einstein.yu.edu john.m.dye1.civ@mail.mil javad@integratedbiotherapeutics.com james.crowe@vanderbilt.edu.
Kartik
K
Chandran
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D001665:Binding Sites / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology*; D045744:Cell Line, Tumor; D029043:Ebolavirus / Q000276:immunology*; D011992:Endosomes / Q000821:virology; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control* / Q000628:therapy; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000077296:Niemann-Pick C1 Protein; D011991:Receptors, Virus / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000276:immunology*; D053586:Virus Internalization
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D011991:Receptors, Virus; D014759:Viral Envelope Proteins; C113189:envelope glycoprotein, Ebola virus