Absence of Adverse Effects in Cynomolgus Macaques Treated with CNTO 95, a Fully Human Anti-αv Integrin Monoclonal Antibody, Despite Widespread Tissue Binding

Martin, Pauline L.; Jiao, Qun; Cornacoff, Joel B.; Hall, William C.; Saville, Bradley A.; Nemeth, Jeffrey A.; Schantz, Allen; Mata, Marielena; Jang, Haishan; Fasanmade, Adedigbo A.; Anderson, Lisa; Graham, Martin A.; Davis, Hugh M.; Treacy, George

doi:10.1158/1078-0432.ccr-04-2623

Cited by 41 publications

(38 citation statements)

References 23 publications

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“…Also, perfluorocarbon-lecithin emulsions have already been approved for clinical use as blood substitutes (Perflubron). Furthermore, integrin antibodies and peptibodies have proved safe in phase 1 and 2 clinical trials (52)(53)(54)(55)(56)(57). Thus, we do not anticipate toxicities from these 2 components of the nanoparticulate system.…”

Section: Discussionmentioning

confidence: 95%

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

Soman¹,

Baldwin²,

Hu³

et al. 2009

J. Clin. Invest.

265

277

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The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.

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Section: Discussionmentioning

confidence: 95%

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

Soman¹,

Baldwin²,

Hu³

et al. 2009

J. Clin. Invest.

265

277

View full text Add to dashboard Cite

show abstract

“…Therefore, caution should be used in extrapolating these safety and toxicity data from rats to human patients. However, data from a preclinical toxicity study in cynomolgus macaques showed that treatment with intetumumab produced no sign of toxicity and no histopathologic changes in any of the tissues examined (2). Data from two recently completed phase I clinical trials (6, 7) further showed that intetumumab was generally safe and well tolerated either alone or in combination with docetaxel in 6-week or prolonged treatment regimens.…”

Section: Discussionmentioning

confidence: 99%

“…1). Preclinical studies have shown that intetumumab exhibits antiangiogenic and antitumor activity in human cancer xenograft models in nude mice (1)(2)(3). Intetumumab has been reported to inhibit cell adhesion, migration, invasion, and proliferation of endothelial cells and tumor cells in vitro and tumor metastasis in vivo in nude mice with human breast cancer xenografts by inactivating the focal adhesion kinase (FAK) and the docking protein paxillin (1,4).…”

Section: Introductionmentioning

confidence: 99%

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

et al. 2010

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We previously reported that intetumumab (CNTO 95), a fully human anti-αv integrin monoclonal antibody, is a radiosensitizer in mice with xenograft tumors. Because intetumumab does not cross-react with mouse integrins, but has cross-reactivity with rat integrins, we next studied the potential combined use of radiation therapy and intetumumab in human cancer xenograft models in nude rats to assess effects on both tumor cells and the tumor microenvironment. Nude rats bearing human head and neck cancer and non-small cell lung cancer (NSCLC) xenografts were treated with intetumumab and fractionated local tumor radiotherapy. Effects on tumor growth and metastasis, blood perfusion, oxygenation, and gastrointestinal toxicity were studied. Intetumumab alone had a moderate effect on tumor growth. When combined with fractionated radiation therapy, intetumumab significantly inhibited tumor growth and produced a tumor response rate that was significantly better than with radiation therapy alone. Treatment with intetumumab also significantly reduced lung metastasis in the A549 NSCLC xenograft model. The oxygenation and blood perfusion in xenograft tumors measured by microbubble-enhanced ultrasound imaging were substantially increased after treatment with intetumumab. The combined use of intetumumab and radiation therapy reduced the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. Toxicity studies showed that treatment with intetumumab did not cause the histopathologic changes in the lungs and did not sensitize the sensitive gastrointestinal epithelium to the effect of radiation therapy. Intetumumab can potentiate the efficacy of fractionated radiation therapy in human cancer xenograft tumors in nude rats without increased toxicity.

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“…4). Preclinical studies have shown that CNTO 95 exhibits antitumor and antiangiogenic activity in human cancer xenograft models when used as a single agent with few adverse effects (4,5). Recently, a phase I study of CNTO 95 in patients with advanced solid tumors has shown that CNTO 95 was well tolerated (6).…”

Section: Introductionmentioning

confidence: 99%

Anti-integrin monoclonal antibody CNTO 95 enhances the therapeutic efficacy of fractionated radiation therapy in vivo

Ning

Nemeth²,

Hanson³

et al. 2008

Molecular Cancer Therapeutics

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Selective targeting of up-regulated integrins on tumor cells is a novel antiangiogenesis strategy for treating solid tumors. CNTO 95 is a fully human anti-A v integrin monoclonal antibody and has shown antitumor activity when used as a single agent in preclinical studies. We previously showed that radiation combined with an integrin A v B 3 antagonist cRGD peptide increased the therapeutic efficacy of radiation in preclinical tumor models. We hypothesized that the combination of radiation and CNTO 95 would synergistically enhance the efficacy of radiation therapy. The in vitro studies showed that CNTO 95 radiosensitized and induced apoptosis in M21 cells in vitronectin-coated dishes. In mice bearing established human cancer xenograft tumors, CNTO 95 alone had only a moderate effect on tumor growth. The combined therapy of CNTO 95 and fractionated radiation significantly inhibited tumor growth and produced the longer tumor growth delay time in multiple tumor models. Maintenance dosing of CNTO 95 following irradiation contributed to efficacy and was important for continued inhibition of tumor regrowth. Immunohistochemistry studies showed that the combined use of CNTO 95 and radiation reduced the A v integrin and vascular endothelial growth factor receptor expression and the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. CNTO 95 alone and in combination with radiation did not produce any obvious signs of systemic toxicity. These results show that CNTO 95 can potentiate the efficacy of fractionated radiation therapy in a variety of human cancer xenograft tumor types in nude mice. These findings are very promising and may have high translational relevance for the treatment of patients with solid tumors. [Mol Cancer Ther 2008;7(6):1569 -78]

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Absence of Adverse Effects in Cynomolgus Macaques Treated with CNTO 95, a Fully Human Anti-αv Integrin Monoclonal Antibody, Despite Widespread Tissue Binding

Cited by 41 publications

References 23 publications

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

Anti-integrin monoclonal antibody CNTO 95 enhances the therapeutic efficacy of fractionated radiation therapy in vivo

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