A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses

Anna Z. Wec, Elisabeth K. Nyakatura, Andrew S. Herbert, Katie A. Howell, Frederick W. Holtsberg, Russell R. Bakken, Eva Mittler, John R. Christin, Sergey Shulenin, Rohit K. Jangra, Sushma Bharrhan, Ana I. Kuehne, Zachary A. Bornholdt, Andrew I. Flyak, Erica Ollmann Saphire, James E. Crowe, M. Javad Aman, John M. Dye, Jonathan R. Lai, Kartik Chandran

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)350-354
Number of pages5
JournalScience
Volume354
Issue number6310
DOIs
StatePublished - Oct 21 2016

Fingerprint

Ebolavirus
Bispecific Antibodies
Monoclonal Antibodies
Endosomes
Virion
Epitopes
Glycoproteins
Binding Sites
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses. / Wec, Anna Z.; Nyakatura, Elisabeth K.; Herbert, Andrew S.; Howell, Katie A.; Holtsberg, Frederick W.; Bakken, Russell R.; Mittler, Eva; Christin, John R.; Shulenin, Sergey; Jangra, Rohit K.; Bharrhan, Sushma; Kuehne, Ana I.; Bornholdt, Zachary A.; Flyak, Andrew I.; Saphire, Erica Ollmann; Crowe, James E.; Aman, M. Javad; Dye, John M.; Lai, Jonathan R.; Chandran, Kartik.

In: Science, Vol. 354, No. 6310, 21.10.2016, p. 350-354.

Research output: Contribution to journalArticle

Wec, AZ, Nyakatura, EK, Herbert, AS, Howell, KA, Holtsberg, FW, Bakken, RR, Mittler, E, Christin, JR, Shulenin, S, Jangra, RK, Bharrhan, S, Kuehne, AI, Bornholdt, ZA, Flyak, AI, Saphire, EO, Crowe, JE, Aman, MJ, Dye, JM, Lai, JR & Chandran, K 2016, 'A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses', Science, vol. 354, no. 6310, pp. 350-354. https://doi.org/10.1126/science.aag3267
Wec, Anna Z. ; Nyakatura, Elisabeth K. ; Herbert, Andrew S. ; Howell, Katie A. ; Holtsberg, Frederick W. ; Bakken, Russell R. ; Mittler, Eva ; Christin, John R. ; Shulenin, Sergey ; Jangra, Rohit K. ; Bharrhan, Sushma ; Kuehne, Ana I. ; Bornholdt, Zachary A. ; Flyak, Andrew I. ; Saphire, Erica Ollmann ; Crowe, James E. ; Aman, M. Javad ; Dye, John M. ; Lai, Jonathan R. ; Chandran, Kartik. / A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses. In: Science. 2016 ; Vol. 354, No. 6310. pp. 350-354.
@article{0d6b269634a44ec39f1bc22b8fe3b912,
title = "A {"}Trojan horse{"} bispecific-antibody strategy for broad protection against ebolaviruses",
abstract = "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.",
author = "Wec, {Anna Z.} and Nyakatura, {Elisabeth K.} and Herbert, {Andrew S.} and Howell, {Katie A.} and Holtsberg, {Frederick W.} and Bakken, {Russell R.} and Eva Mittler and Christin, {John R.} and Sergey Shulenin and Jangra, {Rohit K.} and Sushma Bharrhan and Kuehne, {Ana I.} and Bornholdt, {Zachary A.} and Flyak, {Andrew I.} and Saphire, {Erica Ollmann} and Crowe, {James E.} and Aman, {M. Javad} and Dye, {John M.} and Lai, {Jonathan R.} and Kartik Chandran",
year = "2016",
month = "10",
day = "21",
doi = "10.1126/science.aag3267",
language = "English (US)",
volume = "354",
pages = "350--354",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6310",

}

TY - JOUR

T1 - A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses

AU - Wec, Anna Z.

AU - Nyakatura, Elisabeth K.

AU - Herbert, Andrew S.

AU - Howell, Katie A.

AU - Holtsberg, Frederick W.

AU - Bakken, Russell R.

AU - Mittler, Eva

AU - Christin, John R.

AU - Shulenin, Sergey

AU - Jangra, Rohit K.

AU - Bharrhan, Sushma

AU - Kuehne, Ana I.

AU - Bornholdt, Zachary A.

AU - Flyak, Andrew I.

AU - Saphire, Erica Ollmann

AU - Crowe, James E.

AU - Aman, M. Javad

AU - Dye, John M.

AU - Lai, Jonathan R.

AU - Chandran, Kartik

PY - 2016/10/21

Y1 - 2016/10/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84988696751&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84988696751&partnerID=8YFLogxK

U2 - 10.1126/science.aag3267

DO - 10.1126/science.aag3267

M3 - Article

C2 - 27608667

AN - SCOPUS:84988696751

VL - 354

SP - 350

EP - 354

JO - Science

JF - Science

SN - 0036-8075

IS - 6310

ER -