Mini reviewTherapeutic potential of anti-HIV immunotoxins
Introduction
The treatment of AIDS and HIV infection has three major goals: antiviral therapy aimed at eliminating HIV, the prevention and treatment of opportunistic infections and malignancies associated with AIDS, and immune restoration to correct the damage to the immune system caused by HIV. This review is concerned with the first aspect of AIDS therapy, the development of anti-HIV drugs. Two classes of HIV-specific antivirals are already approved for use: reverse transcriptase and protease inhibitors, and combinations of these drugs appear more efficacious than when each is used individually (Collier et al., 1996). Despite these advances, there are still significant limitations to existing anti-HIV therapies, especially the evolution of drug-resistant variants. It is therefore essential that the quest for new antivirals continue, particularly for agents with different modes of action and which may eliminate viral reservoirs not eradicated by other agents.
Immunotoxins are bifunctional molecules, consisting of a targeting portion and the toxic moiety, generally either a plant or bacterial toxin (Pincus and Tolstikov, 1995). Immunotoxins are part of a broader class of agents termed immunoconjugates, in which other agents, such as radionuclides or cytotoxic drugs, are coupled to the targeting moiety. These agents have been used effectively and with little toxicity in the treatment of malignancies, graft rejection, and autoimmune diseases (Kaminski et al., 1993; Press et al., 1993; Strand et al., 1993; Frankel et al., 1996; Thrush et al., 1996).
The object of using immunotoxins to treat AIDS is to eliminate HIV-infected cells that are actively secreting virus and spreading infection. Immunotoxins may be targeted either to viral antigens on the surface of HIV-infected cells (referred to as anti-HIV immunotoxins) or to cellular molecules that define the cell type(s) in which HIV replicates. In vitro analyses demonstrate that anti-HIV immunotoxins are highly effective in eliminating infected cells and inhibiting the spread of infection through a cell culture. Significant enhancement of anti-HIV activity has been shown to occur when immunotoxins are used in combination with other antivirals, soluble CD4, or agents that inhibit the intracellular degradation of immunotoxins.
A clinical trial has been performed utilizing a chimeric CD4-toxin molecule. Little evidence of anti-HIV efficacy was demonstrated. However, this immunotoxin had significant drawbacks that may have limited its therapeutic utility. Because of this failure, interest in the use of anti-HIV immunotoxins has diminished. On the basis of in vitro data, nonspecific toxicity, and pharmacokinetics, antibody-based anti-gp41 immunotoxins used in combination with CD4-Ig chimeras have a much higher likelihood of success. Immunotoxins should not be abandoned as a possible treatment for HIV infection. Potential advantages include a different mode of action than existing antivirals, decreased likelihood of inducing infectious drug-resistant variants, and a high therapeutic index.
Section snippets
Immunotoxin structure and design
An immunotoxin functions by binding to the target cell, becoming internalized, and exerting a toxic action which kills the cell. Immunotoxins consist of three portions: the targeting moiety, the toxic substance, and a linker joining the two. Alternatively, the immunotoxin may be a chimeric protein in which the targeting and toxic portions are combined into a single molecule using recombinant DNA technology. The majority of this review is devoted to targeting moiety. The following paragraphs in
Immunotoxins targeted to HIV antigens
The only HIV antigens that are expressed intact on infected cells and recognizable by antibodies are the envelope glycoproteins gp120 (extracellular) and gp41 (transmembrane). Although there is a high degree of inter-isolate sequence variability, there are also highly conserved constant regions in both gp120 and gp41. A number of human and murine monoclonal antibodies have been made against these epitopes. The well conserved CD4-binding region can also be targeted with CD4 itself. Many of the
Immunotoxins directed against the IL-2 receptor or other cellular markers
An alternative approach to deliver immunotoxins to HIV-infected cells is to use cell surface markers that define the subset of cells in which HIV replicates. The IL-2 receptor defines a subset of T cells that are in an activated state. The IL-2 receptor may be targeted with monoclonal antibodies (anti-CD25) or with IL-2 itself. Studies with immunotoxins have clearly demonstrated that in cultures of peripheral blood mononuclear cells, cells expressing the IL-2 receptor are the primary, if not
Clinical studies with CD4-PE40
For a number of reasons, CD4-PE40 appeared to be an ideal candidate for clinical testing. These include scientific rationale such as the broad reactivity of CD4-PE40 with all HIV isolates and potent in vitro activity (Chaudhary et al., 1988; Ashorn et al., 1990, Ashorn et al., 1991; Kennedy et al., 1993), as well as economic ones, such as patent coverage and production in bacterial fermentation cultures. Pharmaceutical grade CD4-PE40 was manufactured by Upjohn Laboratories and clinical trials
Advantages and pitfalls of immunotoxin therapy
The development of drug-resistant HIV variants has been a major factor limiting the utility of antiviral drugs in treating AIDS. Such variants can arise within weeks of the initiation of therapy. Throughout its evolution, HIV has been under continuous immunologic pressure and immunologic escape variants have been shown to occur. Despite this, there are surface-exposed epitopes on both gp120 and gp41 that have remained constant and are well-conserved on different viral isolates. Antibodies to
Future directions
Two avenues are currently being explored. The first is the continuation of ongoing clinical trials with the chimeric IL2-DT. The other is to initiate clinical trials with an anti-HIV immunotoxin.
Phase I trials have shown that IL2-DT is safe in AIDS patients at doses that have been shown to be effective in treating autoimmune disease and malignancy. Efficacy of this immunotoxin will now be tested in Phase II trials, measuring both plasma viremia and disease progression as outcomes.
On the other
References (39)
- Allaway, G.P., Davis-Bruno, K.L., Beaudry, G.A. et al. (1995) Expression and characterization of CD4-IgG2, a novel...
- Amlot, P.L., Stone, M.J., Cunningham, D. et al. (1993) A phase I study of an anti-CD22-deglycosylated ricin A chain...
- Ashorn, P., Moss, B., Weinstein, J.N. et al. (1990) Elimination of infectious human immunodeficiency virus from human...
- Ashorn, P., Englund, G., Martin, M.A., Moss, B. and Berger, E.A. (1991) Anti-HIV activity of CD4-Pseudomonas exotoxin...
- Bell, K.D., Ramilo, O. and Vitetta, E.S. (1993) Combined use of an immunotoxin and cyclosporine to prevent both...
- Borvak, J., Chou, C.-S., Bell, K., Van Dyke, G., Zola, H., Ramilio, O. and Vitetta, E.S. (1995) Expression of CD25...
- Chaudhary, V.K., Mizukami, T., Fuerst, T.R., FitzGerald, D.J., Moss, B., Pastan, I. and Berger, E.A. (1988) Selective...
- Chen, S.-Y., Zani, C., Khouri, Y. and Marasco, W.A. (1995) Design of a genetic immunotoxin to eliminate toxin...
- Collier, A.C., Coombs, R.W., Schoenfeld, D.A. et al. (1996) Treatment of HIV infection with Saquinavir, Zidovudine, and...
- Davey, R.T., Boenning, C.M., Herpin, B.R. et al. (1994) Recombinant soluble CD4-pseudomonas exotoxin, a novel...
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