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

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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

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Wec, A. Z., Nyakatura, E. K., Herbert, A. S., Howell, K. A., Holtsberg, F. W., Bakken, R. R., Mittler, E., Christin, J. R., Shulenin, S., Jangra, R. K., Bharrhan, S., Kuehne, A. I., Bornholdt, Z. A., Flyak, A. I., Saphire, E. O., Crowe, J. E., Aman, M. J., Dye, J. M., Lai, J. R., & Chandran, K. (2016). A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses. Science, 354(6310), 350-354. https://doi.org/10.1126/science.aag3267