Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity

Guillemard, Véronique; Saragovi, H. Uri

doi:10.1038/sj.onc.1207463

Cited by 54 publications

(37 citation statements)

References 31 publications

(32 reference statements)

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“…We hypothesize that P-glycoprotein-mediated efflux could be circumvented by delivering drugs (e.g., doxorubicin) via a rapidly internalizing antibody (hLL1) to CD74-positive tumor cells, thus bypassing the activity of multidrug resistance transporters. Indeed, a recent study reported that an immunoconjugate composed of doxorubicin conjugated to an antibody against insulin-like growth factor receptor allowed bypassing of the P-glycoprotein-mediated resistance ex vivo and in vivo (24). Hence, the role of IMMU-110 in reversing P-glycoproteinmediated resistance will be the subject of future studies.…”

Section: Discussionmentioning

confidence: 99%

Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograft and in Monkeys

Sapra

Stein²,

Pickett³

et al. 2005

Clinical Cancer Research

157

110

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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. 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 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. 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.

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Section: Discussionmentioning

confidence: 99%

Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograft and in Monkeys

Sapra

Stein²,

Pickett³

et al. 2005

Clinical Cancer Research

157

110

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“…ADCs deliver their cytotoxic payload inside cells via antigen-mediated endocytosis, thus bypassing the first MDR1 mechanism (16,18). Upon intracellular processing, conjugates are processed into cytotoxic metabolites, whose structures depend on the chemistry of the linker between the cytotoxic compound and the antibody (19,20).…”

Section: Introductionmentioning

confidence: 99%

Antibody-Maytansinoid Conjugates Designed to Bypass Multidrug Resistance

et al. 2010

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Conjugation of cytotoxic compounds to antibodies that bind to cancer-specific antigens makes these drugs selective in killing cancer cells. However, many of the compounds used in such antibody-drug conjugates (ADC) are substrates for the multidrug transporter MDR1. To evade the MDR1-mediated resistance, we conjugated the highly cytotoxic maytansinoid DM1 to antibodies via the maleimidyl-based hydrophilic linker PEG 4 Mal. Following uptake into target cells, conjugates made with the PEG 4 Mal linker were processed to a cytotoxic metabolite that was retained by MDR1-expressing cells better than a metabolite of similar conjugates prepared with the nonpolar linker N-succinimidyl-4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC). In accord, PEG 4 Mal-linked conjugates were more potent in killing MDR1-expressing cells in culture. In addition, PEG 4 Mal-linked conjugates were markedly more effective in eradicating MDR1-expressing human xenograft tumors than SMCC-linked conjugates while being tolerated similarly, thus showing an improved therapeutic index. This study points the way to the development of ADCs that bypass multidrug resistance.

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“…A variety of targeting ligands, including antibodies, antibody fragments, peptides, growth factors, and aptamers (64), have been used to facilitate the uptake of carriers into target cells (65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76).…”

Section: Selection Of Target Receptor and Ligandmentioning

confidence: 99%

Advances of Cancer Therapy by Nanotechnology

et al. 2009

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Recent developments in nanotechnology offer researchers opportunities to significantly transform cancer therapeutics. This technology has enabled the manipulation of the biological and physicochemical properties of nanomaterials to facilitate more efficient drug targeting and delivery. Clinical investigations suggest that therapeutic nanoparticles can enhance efficacy and reduced side effects compared with conventional cancer therapeutic drugs. Encouraged by rapid and promising progress in cancer nanotechnology, researchers continue to develop novel and efficacious nanoparticles for drug delivery. The use of therapeutic nanoparticles as unique drug delivery systems will be a significant addition to current cancer therapeutics.

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Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity

Cited by 54 publications

References 31 publications

Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograft and in Monkeys

Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograft and in Monkeys

Antibody-Maytansinoid Conjugates Designed to Bypass Multidrug Resistance

Advances of Cancer Therapy by Nanotechnology

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