Targeted delivery of anti-CD19 liposomal doxorubicin in B-cell lymphoma: a comparison of whole monoclonal antibody, Fab' fragments and single chain Fv

J Control Release. 2008 Feb 18;126(1):50-8. doi: 10.1016/j.jconrel.2007.11.005. Epub 2007 Nov 17.

Abstract

As part of an ongoing effort to develop a clinically acceptable doxorubicin formulation, targeted against B-cell malignancies, this study compared long-circulating (Stealth) immunoliposomes (SIL) that were targeted against the B-cell antigen CD19, via a whole HD37 monoclonal antibody (HD37 mAb), versus its Fab' fragment (HD37 Fab') or an HD37-c-myc-Cys-His5 single chain Fv fragment (scFv, HD37-CCH) directed against the same epitope. Compared to untargeted liposomes (SL), SIL showed increased binding in vitro to CD19-expressing Raji cells and, when loaded with doxorubicin (SIL-DXR), increased cytotoxicity against Raji (CD19(+)), but not Molt4 (CD19(-)) cells. Pharmacokinetics and biodistribution studies using dual-labeled liposomes (lipid and drug) in naive and Raji-bearing mice showed that SIL-DXR targeted via HD37 Fab' exhibited the same long circulation half-life as SL-DXR. SIL-DXR targeted via HD37-CCH was cleared faster than SL-DXR due to increased liver uptake, which was related to the poly-His and/or the c-myc tags in the scFv construct. SIL-DXR targeted via HD37 mAb was cleared rapidly from circulation due to Fc-mediated uptake in the liver and spleen. All three formulations of SIL-DXR extended the mean survival time of Raji-bearing mice compared to SL-DXR or free DXR. SIL-DXR targeted via HD37 Fab', which had the longest circulation half-life, appeared to be slightly more effective in prolonging survival times than SIL-DXR targeted via either HD37-CCH or HD37 mAb.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage*
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / therapeutic use
  • Antibodies, Monoclonal* / administration & dosage
  • Antibodies, Monoclonal* / pharmacokinetics
  • Antibodies, Monoclonal* / therapeutic use
  • Antigens, CD19 / immunology*
  • Burkitt Lymphoma / drug therapy
  • Burkitt Lymphoma / immunology
  • Burkitt Lymphoma / metabolism*
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Doxorubicin / administration & dosage*
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / therapeutic use
  • Female
  • Humans
  • Immunoglobulin Fab Fragments* / administration & dosage
  • Immunoglobulin Fab Fragments* / therapeutic use
  • Liposomes
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Nanoparticles
  • Neoplasm Transplantation
  • Tissue Distribution

Substances

  • Antibiotics, Antineoplastic
  • Antibodies, Monoclonal
  • Antigens, CD19
  • Immunoglobulin Fab Fragments
  • Liposomes
  • Doxorubicin