Improved therapeutic responses in a xenograft model of human B lymphoma (Namalwa) for liposomal vincristine versus liposomal doxorubicin targeted via anti-CD19 IgG2a or Fab' fragments.

Abstract

PURPOSE:

Monoclonal antibody-mediated targeting of liposomal anticancer drugs to surface antigens expressed on malignant B cells can be an effective strategy for treating B-cell malignancies. In a murine model of human B-cell lymphoma, we have made in vitro and in vivo comparisons of long-circulating sterically stabilized (Stealth) immunoliposome (SIL) formulations of two anticancer drugs, vincristine (VCR) and doxorubicin (DXR), with different mechanisms of action and drug release rates.

EXPERIMENTAL DESIGN:

SIL formulations of VCR or DXR were conjugated to the monoclonal antibody anti-CD19 (SIL[alphaCD19]) or its Fab' fragments (SIL[Fab']). Specific binding of SILs to Namalwa cells was studied using radiolabeled liposomes, and cytotoxicities of DXR- or VCR-loaded SILs were quantitated by a tetrazolium assay. Pharmacokinetic and drug leakage experiments were performed in mice using dual-labeled liposomes, and the therapeutic responses of SILs were evaluated in a Namalwa (human B lymphoma) cell xenograft model.

RESULTS:

SIL[alphaCD19] or SIL[Fab'] had higher association with and cytotoxicity against Namalwa cells than nontargeted liposomes. SIL[Fab'] had longer circulation times than SIL[alphaCD19], and VCR had faster release rates from the liposomes than DXR. SIL formulations of either VCR or DXR had significantly better therapeutic outcomes than nontargeted liposomes or free drugs. SILs loaded with VCR were superior to those loaded with DXR. SIL[Fab'] had better therapeutic outcomes than SIL[alphaCD19] for the drug DXR but were equally efficacious for the drug VCR.

CONCLUSIONS:

Treatment of a B lymphoma model with single injections of anti-CD19-targeted liposomal formulations of VCR resulted in high levels of response and long-term survivors. Responses to anti-CD19-targeted liposomal DXR were more modest, although the longer circulation times of SIL[Fab'] versus SIL[alphaCD19] led to superior therapeutics for DXR-loaded immunoliposomes.

• Authors: Puja Sapra, Elaine H Moase, Jie Ma, Theresa M Allen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 3 Pg. 1100-11 (Feb 01 2004) ISSN: 1078-0432 [Print] United States
• PMID: 14871990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Antibodies, Monoclonal
• Antigens, CD19
• Antineoplastic Agents, Phytogenic
• Immunoglobulin Fragments
• Immunoglobulin G
• Liposomes
• Tetrazolium Salts
• Thiazoles
• Vincristine
• Doxorubicin
• thiazolyl blue

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacokinetics)
• Antibodies, Monoclonal (chemistry)
• Antigens, CD19 (biosynthesis)
• Antineoplastic Agents, Phytogenic (pharmacokinetics)
• Cell Line, Tumor
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacokinetics)
• Female
• Humans
• Immunoglobulin Fragments (chemistry)
• Immunoglobulin G (chemistry)
• Inhibitory Concentration 50
• Liposomes (chemistry, metabolism)
• Lymphoma, B-Cell (drug therapy, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Neoplasm Transplantation
• Tetrazolium Salts (pharmacology)
• Thiazoles (pharmacology)
• Time Factors
• Vincristine (pharmacokinetics)