Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.

Lynch, Thomas J.; Lambert, JM; Coral, F; Shefner, Jeremy M.; Wen, Patrick Y.; Blättler, Walter A.; Collinson, Albert R.; Ariniello, P D; Braman, G; Cook, Sherrilyn; Esseltine, Dixie Lee; Elias, Alby; Skarin, Arthur T.; Ritz, Jérôme

doi:10.1200/jco.1997.15.2.723

Cited by 69 publications

(30 citation statements)

References 22 publications

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“…The immunoconjugate N901-bR showed potent cytotoxicity against CD56 ϩ SCLC cells in preclinical studies. Importantly, in a Phase I study treating patients with relapsed SCLC, N901-bR was well tolerated with acceptable toxicity (48) and potential clinical activity. In addition, immunohistochemical staining of tissue samples from patients receiving infusion of N901-bR has demonstrated the selective binding of the immunotoxin to target tumor SCLC cells located in the BM and other tissues (48).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, in a Phase I study treating patients with relapsed SCLC, N901-bR was well tolerated with acceptable toxicity (48) and potential clinical activity. In addition, immunohistochemical staining of tissue samples from patients receiving infusion of N901-bR has demonstrated the selective binding of the immunotoxin to target tumor SCLC cells located in the BM and other tissues (48). This study suggested that mAb N901 linked to a cytotoxic agent can recognize and target CD56 ϩ tumor cells in vivo, in particular in a setting of a disseminated human disease involving BM localization.…”

Section: Discussionmentioning

confidence: 99%

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In Vitroandin VivoActivity of the Maytansinoid Immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells

et al. 2004

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ABSTRACT؉ OPM2 human MM cell line in SCID mice. We observed inhibition of serum paraprotein secretion, inhibition of tumor growth, and increase in survival of mice treated with huN901-DM1. Our data therefore demonstrate that huN901-DM1 has significant in vitro and in vivo antimyeloma activity at doses that are well tolerated in a murine model. Taken together, these data provide the framework for clinical trials of this agent to improve patient outcome in MM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In Vitroandin VivoActivity of the Maytansinoid Immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells

et al. 2004

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“…In a phase I study in 21 patients with relapsed or refractory SCLC, only one patient showed PR out of the 20 patients that have been evaluated. This trial was last reported in 1997 [130][131][132]. The phase II trial in nine SCLC patients was unsuccessful, since no objective response to N901-bR was observed.…”

Section: N901-brmentioning

confidence: 99%

Antibody-Based Immunotoxins for the Treatment of Cancer

Becker

Benhar

2012

Antibodies

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Antibody-based immunotoxins comprise an important group in targeted cancer therapeutics. These chimeric proteins are a form of biological guided missiles that combine a targeting moiety with a potent effector molecule. The targeting moiety is mostly a monoclonal antibody (MAb) or a recombinant antibody-based fragment that confers target specificity to the immunotoxin. The effector domain is a potent protein toxin of bacterial or plant origin, which, following binding to the target cells, undergoes internalization and causes cell death. Over time and following research progression, immunotoxins become better fitted to their purpose, losing immunogenic fragments and non-specific targeting moieties. Many immunotoxins have gone through clinical evaluation. Some of these have been shown to be active and work is progressing with them in the form of further clinical trials. Others, mostly developed in the previous century, failed to generate a response in patients, or even caused undesired side effects. This article reviews the antibody and protein-toxin based immunotoxins that were clinically evaluated up to the present day.

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“…The scFv described here may also be a useful reagent in such detection assays and is a starting point for future variants produced by genetic engineering techniques that have improved properties for clinical application. In particular, the design and production of immunotoxins based on this construct could have a significant clinical relevance (43,44). Although C219 is directed toward a cytoplasmic epitope, there are a number of efforts under way to direct compounds to the cytoplasm either by using translocation signals (e.g.…”

Section: Discussionmentioning

confidence: 99%

A Single Chain Fv Fragment of P-glycoprotein-specific Monoclonal Antibody C219

Hoedemaeker

Signorelli

Johns

et al. 1997

Journal of Biological Chemistry

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A construct encoding a single chain variable fragment of the anti-P-glycoprotein monoclonal antibody C219 was made by combining the coding sequences for the heavy and light chain variable domains with a sequence encoding the flexible linker (GGGGS) 3 , an OmpA signal sequence, a c-myc identification tag, and a five-histidine purification tag. The construct was expressed in Escherichia coli and purified from the periplasmic fraction using a nickel chelate column and ion exchange chromatography. Three-step Western blot analysis showed that the construct retains binding affinity for P-glycoprotein. Crystals of 1.0 ؋ 0.2 ؋ 0.2 mm were grown in 100 mM citrate, pH 4.5, 21% polyethylene glycol 6000 in the presence of low concentrations of subtilisin, resulting in proteolytic removal of the linker and purification tags. The structure was solved to a resolution of 2.4 Å with an R factor of 20.6, an R free of 28.5, and good stereochemistry. This result could lead to a clinically useful product based on antibody C219 for the diagnosis of P-glycoprotein-mediated multidrug resistance. The molecule will also be useful in biophysical studies of functional domains of P-glycoprotein, as well as studies of the intact molecule.

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Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.

Cited by 69 publications

References 22 publications

In Vitroandin VivoActivity of the Maytansinoid Immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells

In Vitroandin VivoActivity of the Maytansinoid Immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells

Antibody-Based Immunotoxins for the Treatment of Cancer

A Single Chain Fv Fragment of P-glycoprotein-specific Monoclonal Antibody C219

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