@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",
note = "Funding Information: The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. We thank C. Harold and T. Alkutkar for technical support. We acknowledge M. D. Scharff, S. Buhl, and the Einstein Macromolecular Therapeutics Development Facility for assistance with generation of mAb-548; E. Ndungo for assistance with hybridoma screening and for provision of purified human-Russell's viper NPC1 chimeras; E. L. Snapp and L. Costantini for generating an NPC1-eBFP2 fusion construct; and A. F. Labrijn, P. W. H. I. Parren, and Genmab for the gift of purified b12∗MR72 DuoBody. This work is supported by NIH grants U19 AI109762 (Centers for Excellence in Translational Research) to K.C., J.R.L., J.M.D., and E.O.S.; R01 AI088027 to K.C.; and 1R41 AI122403 to J.R.L. and M.J.A.; Joint Science and Technology Office-Defense Threat Reduction Agency (JSTO-DTRA) project CB04088 to J.M.D.; and a DTRA contract (HDTRA1-13-C-0015) to M.J.A. E.K.N. was also supported by a DAAD (Deutscher Akademischer Austauschdienst, German Academic Exchange Service) fellowship. M.J.A. is president of and owns stocks, and F.W.H. and S.S. own stock options, in Integrated Biotherapeutics. M.J.A., F.W.H., K.A.H., and S.S. are named coinventors on a patent application (WO 2015/200522 A2) submitted by Integrated Biotherapeutics, that covers the endosomal targeting of filovirus bispecific antibodies. A.Z.W., E.K.N., J.R.L., and K.C. are named coinventors on a patent application (PCT/US/16/30652) submitted by Albert Einstein College of Medicine that covers the use of mAb-548 and bispecific antibodies incorporating mAb-548. A.I.F. and J.E.C. are named coinventors on a patent application (PCT/US2016/019644) submitted by Vanderbilt University Medical Center that covers the use of the MR72 antibody and bispecific antibodies incorporating MR72. mAb-548 and bispecific antibodies incorporating it are available from K.C. under a material transfer agreement with Albert Einstein College of Medicine. MR72 antibody and bispecific antibodies incorporating it are available from J.E.C. under a material transfer agreement with Vanderbilt University Medical Center. Publisher Copyright: {\textcopyright} 2016, American Association for the Advancement of Science. All rights reserved.",
year = "2016",
month = oct,
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",
}
