In this application, we are proposing to create a novel class of anti-HIV-1 immunotherapeutics by conjugating HIV-1 fusion inhibitors to exceptionally broadly neutralizing antibodies (bNABS). The cell surface receptors utilized by HIV-1 (CD4, CCR5, CXCR4) are attractive targets for therapy because they are under no pressure to evolve resistance. Unfortunately, HIV envelope protein (Env) mutations are readily evolved to escape small molecule receptor blockade. Likewise, bNABs have been discovered that neutralize up to 90% of tested viral strains but when HIV is challenged with antibodies, in vivo resistance quickly develops. In both cases, the resistance is due to mutations in the Env, although mutations to escape one molecule can make HIV more sensitive to another. Our hypothesis is that a bNAB modified with anti-HIV fusion inhibitor would be an exceptionally potent compound and that a sufficiently modified bNAB would be multifunctional and act as single molecule """"""""cocktail."""""""" Such a compound would make evolution of resistance very difficult for HIV because it would require many mutations to escape the binding sites of the bNABs and the sterically blocked cell receptor sites. We propose to synthesize validated small molecule HIV inhibitors that target the co-receptors CCR5 and CXCR4, as well as, small molecules that bind and disrupt the CD4/gp120 fusion. These compounds will be synthesized linked to protein reactive moieties which will allow for specific modification of bNABs. Our lab has recently developed two different approaches for specific targeting of tyrosine residues for this purpose. The well characterized and very broadly neutralizing antibodies PG9 and VRCO1 will serve as the scaffold for modification. In addition to chemical modification, we will also investigate creating genetic fusions to combine the Fv's of PG9 and VRCO1 onto a single molecule, as well as, engineering the Fc domain to increase in vivo half-life. Multi-specific antibodies will be assessed for their ability to neutralize a broad panel of HIV-1 isolates including strains which are resistant to the bNABs and the small molecule fusion inhibitors. Successful candidate antibodies will then be assayed for half-life and toxicity. Finally, multi-specific antibodies will be used in an HIV escape assay to test our hypothesis that these molecules can pose an evolutionary challenge that HIV cannot answer. We anticipate that the products of this research will be exceptionally potent and broadly active HIV-1 immunotherapeutics and prophylactics.

Public Health Relevance

This proposal aims to develop exceptionally potent and broadly active anti-HIV-1 therapeutics and prophylactics. Although current retroviral drug cocktails are very effective in controlling HIV-1 in most individuals, HIV-1 eventually evolves resistance to all drugs. We propose to create a novel type of chemically modified anti-HIV antibody that blocks HIV-1 entry through multiple mechanisms. This multi-specific immunotherapeutic would provide potent long-lived anti-HIV therapy/prophylaxis and would be very hard for HIV-1 to evolve resistance against.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI095038-01
Application #
8138731
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Conley, Tony J
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
1
Fiscal Year
2011
Total Cost
$473,750
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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