Anti-CD74 antibody-doxorubicin conjugate, IMMU-110, in a human multiple myeloma xenograft and in monkeys.

Abstract

PURPOSE:

IMMU-110 is a drug immunoconjugate composed of doxorubicin conjugated to the humanized anti-CD74 monoclonal antibody, hLL1, at a doxorubicin/monoclonal antibody ratio of approximately 8:1 (mol/mol). CD74 is a rapidly internalizing molecule associated with HLA-DR, which has high expression by several tumor types. Here, we describe safety evaluations of IMMU-110 in mice and monkeys as well as efficacy studies in a xenograft model of the human multiple myeloma cell line, MC/CAR.

EXPERIMENTAL DESIGN:

In vitro binding of IMMU-110 was determined by a cell-based ELISA and cytotoxicity of IMMU-110 assayed with a tetrazolium assay. Pharmacokinetics and biodistribution of radiolabeled IMMU-110 were examined in tumor-free BALB/c mice, and the therapeutic effectiveness was evaluated in severe combined immunodeficient mice bearing MC/CAR cells. Acute toxicity of IMMU-110 was studied in CD74-positive cynomolgus monkeys (Macaca fascicularis).

RESULTS:

In vitro, IMMU-110 specifically binds to CD74 and is cytotoxic against MC/CAR cells. In vivo, IMMU-110 displayed a pharmacokinetic and biodistribution profile identical to that of unconjugated hLL1 monoclonal antibody, except for higher kidney uptake. Treatment with a single dose of IMMU-110 as low as 50 microg antibody/mouse (or 1.4 microg doxorubicin/mouse), 5 days postinjection of the multiple myeloma cells, resulted in cure of most mice. In mice, no host toxicity of IMMU-110 was observed at the highest protein dose tested (125 mg/kg). In cynomolgus monkeys, bone marrow toxicity was observed at 30 and 90 mg/kg doses.

CONCLUSIONS:

The excellent safety and efficacy profile of IMMU-110 supports clinical testing of this immunoconjugate in the treatment of CD74-positive B-cell malignancies.

• Authors: Puja Sapra, Rhona Stein, Jennifer Pickett, Zhengxing Qu, Serengulam V Govindan, Thomas M Cardillo, Hans J Hansen, Ivan D Horak, Gary L Griffiths, David M Goldenberg
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 14 Pg. 5257-64 (Jul 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16033844 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antigens, Differentiation, B-Lymphocyte
• Histocompatibility Antigens Class II
• IMMU-110
• Immunoconjugates
• invariant chain
• Doxorubicin

Topics

• Animals
• Antibodies, Monoclonal (adverse effects, immunology, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antigens, Differentiation, B-Lymphocyte (immunology)
• Doxorubicin (adverse effects, immunology, pharmacokinetics)
• Enzyme-Linked Immunosorbent Assay
• Female
• Haplorhini
• Histocompatibility Antigens Class II (immunology)
• Humans
• Immunoconjugates (adverse effects, immunology, pharmacokinetics)
• Infusions, Intravenous
• Macaca fascicularis
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Multiple Myeloma (drug therapy, immunology, veterinary)
• Tissue Distribution
• Transplantation, Heterologous
• Tumor Cells, Cultured