Fusion Proteins as HIV-1 Entry Inhibitors

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 as promising HIV-1 inhibitors – including in animal models and clinical trials.  However, they have not been successful in human studies 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 previously described a novel bispecific multivalent fusion protein called 4Dm2m which contains a single human CD4 domain (mD1.22) and a potent HIV-1 inhibitor (m36.4) (NIH Reference No. E-033-2013).  mD1.22 is highly soluble and stable with good neutralizing activity without measurable interaction with MHCII.  The NCI inventors have recently discovered new variants of 4Dm2m with increased stability and potency in mediating antibody dependent cellular cytotoxicity (ADCC) against cells expressing the HIV-1 envelope glycoprotein.  The newly identified variants also have increased half-lives in vivo and enhanced antibody binding. 

Potential Commercial Applications: Competitive Advantages:
  • Prophylactic or therapeutic against HIV-1 infection
  • Rapid detection of HIV virus 
  • Increased stability and half-life over previously identified fusion protein 
  • Enhanced potency in mediating ADCC against HIV-1 infected cells
  • Continuous  expression of high levels of these soluble receptors in vivo may overcome biggest challenge to efficacy in patients with HIV-1 infection

Development Stage:
Pre-clinical (in vivo)

Related Invention(s):



Dimiter Dimitrov (NCI)  ➽ more inventions...

Weizao Chen (NCI)  ➽ more inventions...

Tianlei Ying ()  ➽ more inventions...

Intellectual Property:
U.S. Pat: 62/138,003

Chen W, et al. Improving the CH1-CK heterodimerization and pharmacokinetics of 4Dm2m, a novel potent CD4-antibody fusion protein against HIV-1.  PMID: 26963639
Chen W, et al. Exceptionally potent and broadly cross-reactive, bispecific multivalent HIV-1 inhibitors based on single human CD4 and antibody domains.  PMID: 24198429

Collaboration Opportunity:

Licensing only

Licensing Contact:
John Hewes, Ph.D.
Email: John.Hewes@nih.gov
Phone: 240-276-5515

OTT Reference No: E-086-2015
Updated: Jul 27, 2018