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

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 Jr. JE, Aman MJ, Dye JM, Lai JR, Chandran K. 2016. Science 354:350-354

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 post-exposure protection against multiple ebolaviruses in mice. Such ‘Trojan horse’ bispecific antibodies have potential as broad anti-filovirus immunotherapeutics.