Three-in-one antibody protects monkeys from HIV-like virus

2017

Challenge

The human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS) by destroying CD4 positive (CD4+) T cells, a type of white blood cell that is vital to fighting off infection. The destruction of these cells leaves people living with HIV vulnerable to other infections, diseases, and other complications. Nearly 37 million people are living with HIV around the world. The development of an effective HIV vaccine has thus far been challenging, in part due to the virus’s genetic diversity and the difficulty in generating broadly neutralizing antibodies that can help the immune system fight off multiple variants of the virus.

Advance

IRP investigators in collaboration with a pharmaceutical company engineered a single HIV antibody to interact with three independent components of the HIV-1 virus’s outer coating: the CD4 binding site; the membrane proximal external region (MPER); and the V1V2 glycan site. This ‘trispecific’ antibody exhibited higher potency and targeted more HIV variants than any previously described single broadly neutralizing antibody (bnAb). It also showed pharmacokinetics similar to human bnAbs and, in macaque monkeys, granted complete immunity against a mixture of HIV-like viruses that infect non-human primates.

Impact

The use of bnAbs isolated from HIV-infected individuals in the development of an effective HIV vaccine has been limited by potency and breadth of protection. By binding to three different sites on the virus, a trispecific antibody should be harder for HIV to evade compared to natural antibodies that target only one virus component. Trispecific antibodies thus constitute a platform to engage multiple therapeutic targets through a single protein and could be applicable for diverse diseases, including infections, cancer, and autoimmunity. Plans are underway to conduct early-phase clinical trials in healthy people and in people living with HIV in the hope that trispecific antibodies could eventually be used for long-acting HIV prevention and treatment.

Publications

Xu L, Pegu A, Rao E, Doria-Rose N, Beninga J, McKee K, Lord DM, Wei RR, Deng G, Louder M, Schmidt SD, Mankoff Z, Wu L, Asokan M, Beil C, Lange C, Leuschner WD, Kruip J, Sendak R, Kwon YD, Zhou T, Chen X, Bailer RT, Wang K, Choe M, Tartaglia LJ, Barouch DH, O'Dell S, Todd JP, Burton DR, Roederer M, Connors M, Koup RA, Kwong PD, Yang ZY, Mascola JR, Nabel GJ. (2017). Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques. Science. Oct 6;358(6359):85-90.