Sapra, Puja;
Stein, Rhona;
Pickett, Jennifer;
Qu, Zhengxing;
Govindan, Serengulam V.;
Cardillo, Thomas M.;
Hansen, Hans J.;
Horak, Ivan D.;
Griffiths, Gary L.;
Goldenberg, David M.
Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograft and in Monkeys
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Medientyp:
E-Artikel
Titel:
Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograft and in Monkeys
Beteiligte:
Sapra, Puja;
Stein, Rhona;
Pickett, Jennifer;
Qu, Zhengxing;
Govindan, Serengulam V.;
Cardillo, Thomas M.;
Hansen, Hans J.;
Horak, Ivan D.;
Griffiths, Gary L.;
Goldenberg, David M.
Erschienen:
American Association for Cancer Research (AACR), 2005
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>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 ∼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.</jats:p>
<jats:p>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).</jats:p>
<jats:p>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 μg antibody/mouse (or 1.4 μg 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.</jats:p>
<jats:p>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.</jats:p>