title: 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.
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.
  
  
  RESULTS
  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 ((213)Bi) - (213)Bi-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 (213)Bi-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 (213)Bi-2556 group (P = 0.01). Measurement of the blood platelet counts and gross pathology of the treated mice demonstrated the lack of toxicity for (213)Bi-2556.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York, United States of America. ekaterina.dadachova@einstein.yu.edu
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Dadachova
authors.forename: Scott G
authors.initials: SG
authors.lastname: Kitchen
authors.forename: Gregory
authors.initials: G
authors.lastname: Bristol
authors.forename: Gayle Cocita
authors.initials: GC
authors.lastname: Baldwin
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Revskaya
authors.forename: Cyril
authors.initials: C
authors.lastname: Empig
authors.forename: George B
authors.initials: GB
authors.lastname: Thornton
authors.forename: Miroslaw K
authors.initials: MK
authors.lastname: Gorny
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001729:Bismuth; D060740:Disease Eradication / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000821:virology; D051379:Mice; D010537:Peritoneum / Q000166:cytology / Q000276:immunology; D010976:Platelet Count; D011868:Radioisotopes; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D011868:Radioisotopes; C514787:gp41 protein, Human immunodeficiency virus 1; D001729:Bismuth