Selective targeting of immunoliposomal doxorubicin against human multiple myeloma in vitro and ex vivo

Biochim Biophys Acta. 2000 Jun 1;1466(1-2):205-20. doi: 10.1016/s0005-2736(00)00203-0.

Abstract

Circulating malignant CD19(+) B cells have been implicated in the pathogenesis and relapse of multiple myeloma (MM). This study investigated the therapeutic applicability of using long-circulating liposome-encapsulated doxorubicin (DXR) targeted against the internalizing CD19 antigens present on human MM cells. In vitro binding studies using the CD19(+) MM cell line ARH77 demonstrated that CD19-directed immunoliposomes (SIL[anti-CD19]) specifically attached to these cells. Formulations of immunoliposomal doxorubicin (DXR-SIL[anti-CD19]) showed a higher association with, and higher cytotoxicity against, ARH77 cells than did non-targeted liposomal doxorubicin (DXR-SL) or isotype-matched controls (DXR-NSIL[IgG2a]). By using the pH-sensitive fluorophore, 1-hydroxypyrene-3,6, 8-trisulfonic acid, binding of SIL[anti-CD19] to CD19 antigens was shown to trigger receptor-mediated internalization of the antibody-antigen complexes into endosomes. Targeting of SIL[anti-CD19] to CD19(+) B cells was also demonstrated in a heterogeneous mixture of peripheral blood mononuclear cells (PBMC) from MM patients. A decrease in cellular DNA (which is an indicator of apoptosis) caused by the cytotoxicity of DXR-SIL[anti-CD19] to myeloma PBMC was determined by using flow cytometry. While PBMC treatment with free DXR resulted in non-specific cytotoxicity to both B and T cells, DXR-SL were only minimally cytotoxic to either. In contrast, DXR-SIL[anti-CD19] were selectively cytotoxic for B cells in PBMC, indicating that this treatment may be effective in eliminating circulating malignant B cells in MM patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / classification
  • Antigens, CD / immunology
  • Antineoplastic Agents / pharmacology*
  • Cytotoxicity, Immunologic / immunology
  • Doxorubicin / pharmacology*
  • Drug Carriers
  • Humans
  • Immunophenotyping
  • Leukocytes, Mononuclear / immunology
  • Liposomes
  • Mice
  • Multiple Myeloma / drug therapy*
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • Antineoplastic Agents
  • Drug Carriers
  • Liposomes
  • Doxorubicin