Soluble forms of human CD4 (sCD4) inhibit HIV-1 entry into immune cells. Different forms of sCD4 and their fusion proteins have been extensively studied in animal models and clinical trials as promising HIV-1 inhibitors. However, they have not been successful in clinical trials due to their transient efficacy. sCD4 is also known to interact with class II major histocompatibility complex (MHCII) and, at low concentrations, could enhance HIV-1 infectivity.
NCI researchers developed highly soluble, stable single-domain sCD4 with increased neutralizing activity and decreased non-specific binding compared to two-domain sCD4. This invention describes this single-domain sCD4, designated D1, and mutants such as mD1.22 which is highly soluble and stable with good neutralizing activity without measurable interaction with MHCII. The inventors have previously described a novel human domain antibody against HIV-1, designated m36. Due to its small size, this domain antibody targets a hidden CD4-induced (CD4i) epitope on HIV-1 and has the ability to neutralize primary isolates of HIV-1 from different clades more efficiently than full-size antibodies. As part of this invention, the inventors have developed improved domain antibodies based upon the earlier described m36.
NCI researchers have further developed fusion proteins that combine a single human CD4 domain and a potent HIV-1 inhibitor. These fusion proteins exhibit better neutralizing activity than m36 or sCD4 alone.
- Small size of single domain antibodies allows access to areas of HIV-1 that are hidden and inaccessible by larger antibodies
- Decreased non-specific binding of single CD4 domains to MHCII
- Fusion proteins of the inventions have very potent and broad HIV-1 neutralizing activity
- Therapeutic for the treatment of HIV-1 infection