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

@article{citeulike:951467, 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\&\#37; injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99\&\#37; 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.}, author = {Dadachova, Ekaterina and Patel, Mahesh C. and Toussi, Sima and Apostolidis, Christos and Morgenstern, Alfred and Brechbiel, Martin W. and Gorny, Miroslaw K. and Zolla-Pazner, Susan and Casadevall, Arturo and Goldstein, Harris }, citeulike-article-id = {951467}, doi = {http://dx.doi.org/10.1371/journal.pmed.0030427}, journal = {PLoS Medicine}, keywords = {antibody, discovery, drug, mab}, month = {November}, number = {11}, pages = {e427+}, posted-at = {2006-11-19 09:38:44}, priority = {2}, title = {Targeted Killing of Virally Infected Cells by Radiolabeled Antibodies to Viral Proteins}, url = {http://dx.doi.org/10.1371/journal.pmed.0030427}, volume = {3}, year = {2006} }

TY - JOUR ID - citeulike:951467 L3 - citeulike-article-id:951467 TI - Targeted Killing of Virally Infected Cells by Radiolabeled Antibodies to Viral Proteins JF - PLoS Medicine VL - 3 IS - 11 SP - e427 N2 - 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. KW - antibody KW - discovery KW - drug KW - mab AU - Dadachova, Ekaterina AU - Patel, Mahesh AU - Toussi, Sima AU - Apostolidis, Christos AU - Morgenstern, Alfred AU - Brechbiel, Martin AU - Gorny, Miroslaw AU - Zolla-Pazner, Susan AU - Casadevall, Arturo AU - Goldstein, Harris PY - 2006/11/01/ UR - http://dx.doi.org/10.1371/journal.pmed.0030427 ER -