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A Novel Chimeric Bifunctional Protein for Prevention and Treatment of HIV Infection

Posted May 23 2010 5:00pm

Description of Invention:
This invention relates to bifunctional fusion proteins effective in HIV neutralization. Specifically, the invention is a genetically engineered chimeric protein composed of a soluble extracellular region of human CD4 (sCD4) attached via a flexible polypeptide linker to a single-chain construct of a human monoclonal antibody directed against a CD4-induced, highly conserved gp120 determinant involved in co-receptor interaction and virus entry. Mechanistically, the binding of the sCD4 moiety to the HIV gp120 Env glycoprotein induces a conformational change that enables the antibody moiety to bind, thereby blocking Env function and virus entry. This novel design provides the protein with unique characteristics that enables its extremely strong binding to gp120, thus rendering it a potential effective antiviral agent against HIV. Recent studies (Lagenaur et al. Retrovirology 7:11, 2010) indicate that this novel bispecific protein displays extremely broad neutralizing activity against genetically diverse primary HIV-1 isolates, with breadth much greater than previously described (Dey et al. J. Virology 77:2859, 2003). The potency is generally at least 10-fold greater than the best described HIV-1 neutralizing monoclonal antibodies, and the protein is highly active against many HIV-1 isolates that are refractory to neutralization by these antibodies. The bifunctional protein is comparably potent against isogenic virions produced from a human cell line versus PBMC; by contrast, the broadly-reactive monoclonal antibodies are much less potent against virions produced from PBMC, perhaps due to differences in glycosylation. Importantly, the bifunctional protein is composed of almost entirely human sequences. It potentially can be linked to other functional moieties to achieve desired properties (longer plasma half-life, selective killing of HIV-infected cells, imaging of viral reservoirs, etc.). The chimeric protein of this invention has considerable potential for prevention of HIV-1 infection, both as a topical microbicide and as a systemic agent to protect during and after acute exposure (e.g. vertical transmission, post exposure prophylaxis). It also has potential utility for treatment of chronic infection, including gene therapy strategies involving hematopoietic stem cells and/or viral vectors. Such proteins, nucleic acid molecules encoding them, and their production and use in preventing or treating viral infections are claimed in the patents issued for this invention.

Applications:
  • Prophylactic and/or therapeutic treatment for HIV infection
  • Topical microbicide treatment to protect against HIV infection
  • Imaging of HIV infected cells in tissues


Advantages:
  • High neutralization efficiency due to unique bifunctional binding characteristics
  • Potentially minimally immunogenic or toxic (human sequences and possibly low treatment doses)
  • Broad neutralizing activity
  • Mechanism of action less susceptible to resistance


Development Status:
  • Reproducible production and scale-up of chimeric protein has been demonstrated.
  • Potent and broad neutralization of genetically diverse HIV-1 clinical isolates was demonstrated.


Inventors:
Edward A Berger (NIAID)


Patent Status:
HHS, Reference No. E-039-1999/0
US, , Patent No. 7,115,262, Issued 03 Oct 2006
US, Application No. 11/535,957 filed 27 Sep 2006
PCT, Application No. PCT/US00/06946 filed 16 Mar 2000

and related International patents/patent applications

Relevant Publication:
  1. Lagenaur LA, Villarroel VA, Bundoc V, Dey B, Berger EA. sCD4-17b bifunctional protein: extremely broad and potent neutralization of HIV-1 pseudotyped viruses from genetically diverse primary isolates. Retrovirology 2010 Feb 16;7:11. [ PubMed: 20158904 ]
  2. Dey B, Del Castillo CS, Berger EA. Neutralization of human immunodeficiency virus type 1 by sCD4-17b, a single-chain chimeric protein, based on sequential interaction of gp120 with CD4 and coreceptor. J Virol. 2003 March;77(5):2859-2865. [ PubMed: 12584309 ]


Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The NIAID, Office of Technology Development, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize "A Novel Chimeric Bufunctional Protein for Prevention and Treatment of HIV Infection." Please contact Marguerite J. Miller at 301-435-8619 for more information.


Portfolios:
Infectious Diseases
Infectious Diseases - Diagnostics



For Additional Information Please Contact:
Susan Ano Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: anos@mail.nih.gov
Phone: 301-435-5515
Fax: 301-402-0220


Ref No: 73

Updated: 05/2010

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