Targeted Killing of Virally Infected Cells by Radiolabeled Antibodies to Viral Proteins

Ekaterina Dadachova,Miroslaw K Gorny,Susan Zolla-Pazner,Sima Toussi,Christos Apostolidis,Harris Goldstein,Arturo Casadevall,Alfred Morgenstern,Mahesh C Patel,Martin W Brechbiel

doi:10.1371/journal.pmed.0030427

Abstract

BackgroundThe HIV epidemic is a major threat to health in the developing and western worlds. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells. The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo.Methods and FindingsAntibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 (213Bi) and rhenium 188 (188Re) selectively killed chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMCs) in vitro. Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected hPBMCs in their spleens with a 213Bi- or 188Re-labeled monoclonal antibody (mAb) to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner. The number of HIV-1-infected thymocytes decreased 2.5-fold in the human thymic implant grafts of SCID mice treated with the 188Re-labeled antibody to gp41 compared with those treated with the 188Re-control mAb. The treatment did not cause acute hematologic toxicity in the treated mice.ConclusionsThe current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV.

Highlights

The HIV epidemic is a major threat to health in the developing and western worlds
Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected human peripheral blood mononuclear cell (hPBMC) in their spleens with a 213Bi- or 188Re-labeled monoclonal antibody to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner
The current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV

Summary

Introduction

The HIV epidemic is a major threat to health in the developing and western worlds. Highly active antiretroviral therapy (HAART), a combination of drugs that inhibits enzymes essential for HIV-1 replication, can reduce the viremia and the onset of opportunistic infections in most patients and prolong survival [1]. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo. One possible approach that could potentially eradicate HIV in an infected person is to inject antibodies, targeted against elements of the HIV particle, joined to a radioactive ‘‘tag.’’ The idea is that the antibodies would bind to HIV particles at the surface of infected white blood cells, and the radioactivity would kill the infected cell This strategy, called ‘‘radioimmunotherapy,’’ has been successfully used to develop treatments for certain cancers. This is an early step in developing new treatments that would need to show promising results before the approach would be tried in humans

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Results

Conclusion