Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques.

Abstract

The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.

• Authors: Ling Xu, Amarendra Pegu, Ercole Rao, Nicole Doria-Rose, Jochen Beninga, Krisha McKee, Dana M Lord, Ronnie R Wei, Gejing Deng, Mark Louder, Stephen D Schmidt, Zachary Mankoff, Lan Wu, Mangaiarkarasi Asokan, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Jochen Kruip, Rebecca Sendak, Young Do Kwon, Tongqing Zhou, Xuejun Chen, Robert T Bailer, Keyun Wang, Misook Choe, Lawrence J Tartaglia, Dan H Barouch, Sijy O'Dell, John-Paul Todd, Dennis R Burton, Mario Roederer, Mark Connors, Richard A Koup, Peter D Kwong, Zhi-Yong Yang, John R Mascola, Gary J Nabel
• Journal: Science (New York, N.Y.) (Science) Vol. 358 Issue 6359 Pg. 85-90 (10 06 2017) ISSN: 1095-9203 [Electronic] United States
• PMID: 28931639 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• AIDS Vaccines
• Antibodies, Neutralizing
• CD4 Antigens
• HIV Antibodies

Topics

• AIDS Vaccines (administration & dosage, immunology, pharmacokinetics)
• Animals
• Antibodies, Neutralizing (administration & dosage, chemistry, genetics, immunology)
• CD4 Antigens (immunology)
• Crystallography, X-Ray
• HIV Antibodies (administration & dosage, chemistry, genetics, immunology)
• HIV-1 (immunology)
• Humans
• Macaca mulatta
• Protein Engineering
• Simian Acquired Immunodeficiency Syndrome (blood, prevention & control)