Cell Reports (Feb 2018)
Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody
- Young D. Kwon,
- Gwo-Yu Chuang,
- Baoshan Zhang,
- Robert T. Bailer,
- Nicole A. Doria-Rose,
- Tatyana S. Gindin,
- Bob Lin,
- Mark K. Louder,
- Krisha McKee,
- Sijy O’Dell,
- Amarendra Pegu,
- Stephen D. Schmidt,
- Mangaiarkarasi Asokan,
- Xuejun Chen,
- Misook Choe,
- Ivelin S. Georgiev,
- Vivian Jin,
- Marie Pancera,
- Reda Rawi,
- Keyun Wang,
- Rajoshi Chaudhuri,
- Lisa A. Kueltzo,
- Slobodanka D. Manceva,
- John-Paul Todd,
- Diana G. Scorpio,
- Mikyung Kim,
- Ellis L. Reinherz,
- Kshitij Wagh,
- Bette M. Korber,
- Mark Connors,
- Lawrence Shapiro,
- John R. Mascola,
- Peter D. Kwong
Affiliations
- Young D. Kwon
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Gwo-Yu Chuang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Baoshan Zhang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Robert T. Bailer
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Nicole A. Doria-Rose
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Tatyana S. Gindin
- Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
- Bob Lin
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Mark K. Louder
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Krisha McKee
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Sijy O’Dell
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Amarendra Pegu
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Stephen D. Schmidt
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Mangaiarkarasi Asokan
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Xuejun Chen
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Misook Choe
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Ivelin S. Georgiev
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Vivian Jin
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Marie Pancera
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Reda Rawi
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Keyun Wang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Rajoshi Chaudhuri
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Lisa A. Kueltzo
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Slobodanka D. Manceva
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- John-Paul Todd
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Diana G. Scorpio
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
- Mikyung Kim
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
- Ellis L. Reinherz
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
- Kshitij Wagh
- Los Alamos National Laboratory, Los Alamos, NM 87545, USA
- Bette M. Korber
- Los Alamos National Laboratory, Los Alamos, NM 87545, USA
- Mark Connors
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
- Lawrence Shapiro
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
- John R. Mascola
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA; Corresponding author
- Peter D. Kwong
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Corresponding author
- DOI
- https://doi.org/10.1016/j.celrep.2018.01.023
- Journal volume & issue
-
Vol. 22,
no. 7
pp. 1798 – 1809
Abstract
Summary: Highly effective HIV-1-neutralizing antibodies could have utility in the prevention or treatment of HIV-1 infection. To improve the potency of 10E8, an antibody capable of near pan-HIV-1 neutralization, we engineered 10E8-surface mutants and screened for improved neutralization. Variants with the largest functional enhancements involved the addition of hydrophobic or positively charged residues, which were positioned to interact with viral membrane lipids or viral glycan-sialic acids, respectively. In both cases, the site of improvement was spatially separated from the region of antibody mediating molecular contact with the protein component of the antigen, thereby improving peripheral semi-specific interactions while maintaining unmodified dominant contacts responsible for broad recognition. The optimized 10E8 antibody, with mutations to phenylalanine and arginine, retained the extraordinary breadth of 10E8 but with ∼10-fold increased potency. We propose surface-matrix screening as a general method to improve antibodies, with improved semi-specific interactions between antibody and antigen enabling increased potency without compromising breadth.
Keywords
- antibody improvement
- surface-matrix screening
- HIV-1
- broadly neutralizing antibody
- membrane-proximal external region
- MPER
