The development of safe and effective passive immunotherapies for the treatment and prevention of HIV-1 infection is a major goal. The leading candidate immunotherapeutics include the broadly neutralizing human monoclonal antibodies (HuMAbs) IgG1b12, to the CD4-binding site on gp120, 2F5 to a conserved epitope on gp41, and 2g12 to a discontinuous region on gp120. In addition, CD4-IgG2 exhibits potent and broad neutralization of HIV-1, including primary isolates. It is a third generation CD4- based molecule containing two chains of a CD4-human IgG2 heavy chain fusion protein and two chains of a CD4-human kappa light chain fusion protein. While IgG1b12, 2F5, 2G12 and CD4-IgG2 exhibit significant neutralization activity as single agents, the development of an effective passive immunotherapy may require the use of mixtures of two or more of these agents. In order to evaluate their performance in the clinical setting, we have formed a consortium of the three groups which developed these agents (IgG1b12 - Dr. Dennis Burton; 2F5 and 2G12 - Dr. Hermann Katinger; and, CD4-IgG2 - Drs. Graham Allaway and Paul Maddon) to coordinate and expedite clinical trials of single agents and combinations of agents. The goal of this proposal is to manufacture, prepare Investigational New Drug applications and gain regulatory approval for clinical investigation from the U.S. Food and Drug Administration, and perform clinical trials of the agents to evaluate tolerability, antiviral activity, and pharmacology in HIV-1 infected adults and children. As part of our clinical development program, we have already arranged for certain pilot Phase I clinical trials to be performed with single agents in 1997-98 under the sponsorship of the National Institute of Allergy and Infectious Diseases. Based on their performance in clinical trials as well as in in vitro, ex vivo, and animal studies performed as separate projects at the Aaron Diamond AIDS Research Center and the Scripps Research Institute, we will select an optimum combination of 2, 3, or 4 of the agents for evaluation in Phase I/II clinical trials in HIV-1 infected adults and children. If successful, then subsequent to this proposal, the optimum combination would be taken to large-scale, pivotal clinical trials in order to gain marketing approval for the product.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043084-05
Application #
6510836
Study Section
Special Emphasis Panel (ZHL1-CSR-F (S1))
Program Officer
Bridges, Sandra H
Project Start
1998-07-01
Project End
2003-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
5
Fiscal Year
2002
Total Cost
$546,000
Indirect Cost
Name
Progenics Pharmaceuticals, Inc.
Department
Type
DUNS #
945494490
City
Tarrytown
State
NY
Country
United States
Zip Code
10591
Fletcher, Courtney V; DeVille, Jaime G; Samson, Pearl M et al. (2007) Nonlinear pharmacokinetics of high-dose recombinant fusion protein CD4-IgG2 (PRO 542) observed in HIV-1-infected children. J Allergy Clin Immunol 119:747-50
Shearer, William T; DeVille, Jaime G; Samson, Pearl M et al. (2006) Susceptibility of pediatric HIV-1 isolates to recombinant CD4-IgG2 (PRO 542) and humanized mAb to the chemokine receptor CCR5 (PRO 140). J Allergy Clin Immunol 118:518-21
Jacobson, Jeffrey M; Israel, Robert J; Lowy, Israel et al. (2004) Treatment of advanced human immunodeficiency virus type 1 disease with the viral entry inhibitor PRO 542. Antimicrob Agents Chemother 48:423-9
Ketas, Thomas J; Frank, Ines; Klasse, Per Johan et al. (2003) Human immunodeficiency virus type 1 attachment, coreceptor, and fusion inhibitors are active against both direct and trans infection of primary cells. J Virol 77:2762-7
Pincus, Seth H; Fang, Hua; Wilkinson, Royce A et al. (2003) In vivo efficacy of anti-glycoprotein 41, but not anti-glycoprotein 120, immunotoxins in a mouse model of HIV infection. J Immunol 170:2236-41
Zhu, P; Olson, W C; Roux, K H (2001) Structural flexibility and functional valence of CD4-IgG2 (PRO 542): potential for cross-linking human immunodeficiency virus type 1 envelope spikes. J Virol 75:6682-6
Nagashima, K A; Thompson, D A; Rosenfield, S I et al. (2001) Human immunodeficiency virus type 1 entry inhibitors PRO 542 and T-20 are potently synergistic in blocking virus-cell and cell-cell fusion. J Infect Dis 183:1121-5
Jacobson, J M; Lowy, I; Fletcher, C V et al. (2000) Single-dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults. J Infect Dis 182:326-9