title: Exceptionally potent and broadly cross-reactive, bispecific multivalent HIV-1 inhibitors based on single human CD4 and antibody domains.
abstract: Soluble forms of the human immunodeficiency virus type 1 (HIV-1) primary receptor CD4 (soluble CD4 [sCD4]) have been extensively characterized for a quarter of a century as promising HIV-1 inhibitors, but they have not been clinically successful. By combining a protein cavity-filling strategy and the power of library technology, we identified an engineered cavity-altered single-domain sCD4 (mD1.22) with a unique combination of excellent properties, including broad and potent neutralizing activity, high specificity, stability, solubility, and affinity for the HIV-1 envelope glycoprotein gp120, and small molecular size. To further improve its neutralizing potency and breadth, we generated bispecific multivalent fusion proteins of mD1.22 with another potent HIV-1 inhibitor, an antibody domain (m36.4) that targets the coreceptor-binding site on gp120. The fusion proteins neutralized all HIV-1 isolates tested, with potencies about 10-, 50-, and 200-fold higher than those of the broadly neutralizing antibody VRC01, the U.S. FDA-approved peptide inhibitor T20, and the clinically tested sCD4-Fc fusion protein CD4-Ig, respectively. In addition, they exhibited higher stability and specificity and a lower aggregation propensity than CD4-Ig. Therefore, mD1.22 and related fusion proteins could be useful for HIV-1 prevention and therapy, including eradication of the virus.
authors.affiliation: Protein Interactions Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.
authors.forename: Weizao
authors.initials: W
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Ponraj
authors.initials: P
authors.lastname: Prabakaran
authors.forename: Tianlei
authors.initials: T
authors.lastname: Ying
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianping
authors.initials: J
authors.lastname: Sun
authors.forename: Camila D S
authors.initials: CD
authors.lastname: Macedo
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Polonis
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D003429:Cross Reactions; D015483:HIV Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D009500:Neutralization Tests; D061905:Single-Domain Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D061905:Single-Domain Antibodies