Pre-clinical evaluation of a 213Bi-labeled 2556 antibody to HIV-1 gp41 glycoprotein in HIV-1 mouse models as a reagent for HIV eradication

Ekaterina Dadachova, Scott G. Kitchen, Gregory Bristol, Gayle Cocita Baldwin, Ekaterina Revskaya, Cyril Empig, George B. Thornton, Miroslaw K. Gorny, Susan Zolla-Pazner, Arturo Casadevall

Research output: Contribution to journalArticle

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Abstract

Background: Any strategy for curing HIV infection must include a method to eliminate viral-infected cells. Based on our earlier proof-of-principle results targeting HIV-1 infected cells with radiolabeled antibody (mAb) to gp41 viral antigen, we embarked on identifying a suitable candidate mAb for preclinical development. Methodology/Principal Findings: Among the several human mAbs to gp41 tested, mAb 2556 was found to have high affinity, reactivity with multimeric forms of gp41 present on both the surface of virus particles and cells expressing HIV-1 Env, and recognition of a highly conserved epitope of gp41 shared by all HIV-1 subtypes. Also, mAb 2556 was the best in competition with HIV-1+ serum antibodies, which is an extremely important consideration for efficacy in the treatment of HIV patients. When radiolabeled with alpha-emitting radionuclide 213-Bismuth ( 213Bi) - 213Bi-2556 efficiently and specifically killed ACH-2 human lymphocytes chronically infected with HIV-1, and HIV-1 infected human peripheral blood mononuclear cells (hPBMCs). The number of binding sites for 213Bi-2556 on the surface of the infected cells was >10 6. The in vivo experiments were performed in two HIV-1 mouse models - splenic and intraperitoneal. In both models, the decrease in HIV-1 infected hPBMCs from the spleens and peritoneum, respectively, was dose-dependent with the most pronounced killing of hPBMCs observed in the 100 μCi 213Bi-2556 group (P = 0.01). Measurement of the blood platelet counts and gross pathology of the treated mice demonstrated the lack of toxicity for 213Bi-2556. Conclusions/Significance: We describe the preclinical development of a novel radiolabeled mAb reagent that could potentially be part of an HIV eradication strategy that is ready for translation into the clinic as the next step in its development. As viral antigens are very different from "self" human antigens - this approach promises high selectivity, increased efficacy and low toxicity, especially in comparison to immunotoxins.

Original languageEnglish (US)
Article numbere31866
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 9 2012

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bismuth
Bismuth
Human immunodeficiency virus 1
HIV-1
glycoproteins
Glycoproteins
animal models
HIV
Blood
antibodies
Antibodies
Viral Antigens
mononuclear leukocytes
Toxicity
Blood Cells
viral antigens
Immunotoxins
Lymphocytes
Pathology
Platelets

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dadachova, E., Kitchen, S. G., Bristol, G., Baldwin, G. C., Revskaya, E., Empig, C., ... Casadevall, A. (2012). Pre-clinical evaluation of a 213Bi-labeled 2556 antibody to HIV-1 gp41 glycoprotein in HIV-1 mouse models as a reagent for HIV eradication. PLoS One, 7(3), [e31866]. https://doi.org/10.1371/journal.pone.0031866

Pre-clinical evaluation of a 213Bi-labeled 2556 antibody to HIV-1 gp41 glycoprotein in HIV-1 mouse models as a reagent for HIV eradication. / Dadachova, Ekaterina; Kitchen, Scott G.; Bristol, Gregory; Baldwin, Gayle Cocita; Revskaya, Ekaterina; Empig, Cyril; Thornton, George B.; Gorny, Miroslaw K.; Zolla-Pazner, Susan; Casadevall, Arturo.

In: PLoS One, Vol. 7, No. 3, e31866, 09.03.2012.

Research output: Contribution to journalArticle

Dadachova, E, Kitchen, SG, Bristol, G, Baldwin, GC, Revskaya, E, Empig, C, Thornton, GB, Gorny, MK, Zolla-Pazner, S & Casadevall, A 2012, 'Pre-clinical evaluation of a 213Bi-labeled 2556 antibody to HIV-1 gp41 glycoprotein in HIV-1 mouse models as a reagent for HIV eradication', PLoS One, vol. 7, no. 3, e31866. https://doi.org/10.1371/journal.pone.0031866
Dadachova, Ekaterina ; Kitchen, Scott G. ; Bristol, Gregory ; Baldwin, Gayle Cocita ; Revskaya, Ekaterina ; Empig, Cyril ; Thornton, George B. ; Gorny, Miroslaw K. ; Zolla-Pazner, Susan ; Casadevall, Arturo. / Pre-clinical evaluation of a 213Bi-labeled 2556 antibody to HIV-1 gp41 glycoprotein in HIV-1 mouse models as a reagent for HIV eradication. In: PLoS One. 2012 ; Vol. 7, No. 3.
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AU - Revskaya, Ekaterina

AU - Empig, Cyril

AU - Thornton, George B.

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