Design and in vivo characterization of immunoconjugates targeting HIV gp160

Seth H. Pincus, Kejing Song, Grace A. Maresh, Anderson Frank, David Worthylake, Hye Kyung Chung, Patricia Polacino, Dean H. Hamer, Cody P. Coyne, Michael G. Rosenblum, John W. Marks, Gang Chen, Deborah Weiss, Victor Ghetie, Ellen S. Vitetta, James E. Robinson, Shiu Lok Hu

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The envelope (Env) glycoprotein of HIV is expressed on the surface of productively infected cells and can be used as a target for cytotoxic immunoconjugates (ICs), in which cell-killing moieties, including toxins, drugs, or radionuclides, are chemically or genetically linked to monoclonal antibodies (MAbs) or other targeting ligands. Such ICs could be used to eliminate persistent reservoirs of HIV infection. We have found that MAbs which bind to the external loop of gp41, e.g., MAb 7B2, make highly effective ICs, particularly when used in combination with soluble CD4. We evaluated the toxicity, immunogenicity, and efficacy of the ICs targeted with 7B2 in mice and in simian-human immunodeficiency virus-infected macaques. In the macaques, we tested immunotoxins (ITs), consisting of protein toxins bound to the targeting agent. ITs were well tolerated and initially efficacious but were ultimately limited by their immunogenicity. In an effort to decrease immunogenicity, we tested different toxic moieties, including recombinant toxins, cytotoxic drugs, and tubulin inhibitors. ICs containing deglycosylated ricin A chain prepared from ricin toxin extracted from castor beans were the most effective in killing HIVinfected cells. Having identified immunogenicity as a major concern, we show that conjugation of IT to polyethylene glycol limits immunogenicity. These studies demonstrate that cytotoxic ICs can target virus-infected cells in vivo but also highlight potential problems to be addressed.

Original languageEnglish (US)
Article numbere01360-16
JournalJournal of virology
Volume91
Issue number3
DOIs
StatePublished - 2017

Keywords

  • Antibody drug conjugate
  • Human immunodeficiency virus
  • Immunoglobulins
  • Immunotoxins
  • Monoclonal antibodies

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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