<i>In vitro</i>cytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2

Michel, Rosana B.; Andrews, Philip M.; Castillo, Mary Ellen; Mattes, M. Jules

doi:10.1158/1535-7163.mct-04-0340

Cited by 19 publications

(9 citation statements)

References 26 publications

(39 reference statements)

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“…The dramatically enhanced cytotoxic effects of 111 In-NLS-trastuzumab compared with unlabeled trastuzumab found in this study-if translated into in vivo antitumor effects-suggest that this radiotherapeutic agent could potentially offer a more effective treatment for HER2/neu-positive metastatic BC. 111 In-Labeled 4D5 and 21.1 murine mAbs specific for HER2/neu have been found previously to be effective for killing SK-BR-3 breast and SK-OV-3.ip1 ovarian carcinoma cells, either alone or in combination (25). We anticipated that the cytotoxic effects of 111 In-trastuzumab (humanized version of 4D5) would be equally as effective as its 111 In-labeled 4D5 murine counterpart.…”

Section: Discussionmentioning

confidence: 99%

111In-Labeled Trastuzumab (Herceptin) Modified with Nuclear Localization Sequences (NLS): An Auger Electron-Emitting Radiotherapeutic Agent for HER2/neu-Amplified Breast Cancer

Costantini¹,

Chan²,

Cai³

et al. 2007

Journal of Nuclear Medicine

166

176

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The cytotoxicity and tumor-targeting properties of the anti-HER2/neu monoclonal antibody trastuzumab modified with peptides (CGYGPKKKRKVGG) harboring the nuclear localization sequence ([NLS] italicized) of simian virus 40 large T-antigen and radiolabeled with 111 In were evaluated. Methods: Trastuzumab was derivatized with sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC) for reaction with NLSpeptides and labeled with 111 In using diethylenetriaminepentaacetic acid (DTPA). The immunoreactivity of 111 In-NLS-trastuzumab was determined by its ability to displace the binding of trastuzumab to SK-BR-3 human breast cancer (BC) cells. Cellular uptake and nuclear localization were evaluated in SK-BR-3, MDA-MB-361, and MDA-MB-231 BC cells, expressing high, intermediate, or very low levels of HER2/neu, respectively, by cell fractionation and confocal microscopy. Biodistribution and nuclear uptake were compared in athymic mice bearing MDA-MB-361 xenografts. The cytotoxicity of 111 In-trastuzumab and 111 In-NLS-trastuzumab was studied by clonogenic assays, and DNA damage was assessed by probing for phosphorylated histone H2AX (gH2AX) foci. Results: The dissociation constant for binding of 111 In-NLS-trastuzumab to SK-BR-3 cells was reduced ,3-fold compared with that of 111 In-trastuzumab, demonstrating relatively preserved receptorbinding affinity. The receptor-mediated internalization of 111 Intrastuzumab in SK-BR-3, MDA-MB-361, and MDA-MB-231 cells increased significantly from 7.2% 6 0.9%, 1.3% 6 0.1%, and 0.2% 6 0.05% to 14.4% 6 1.8%, 6.3% 6 0.2%, and 0.9% 6 0.2% for 111 In-NLS-trastuzumab harboring 6 NLS-peptides, respectively. NLS-trastuzumab localized in the nuclei of BC cells, whereas unmodified trastuzumab remained surface-bound. Conjugation of 111 In-trastuzumab to NLS-peptides did not affect its tissue biodistribution but promoted specific nuclear uptake in MDA-MB-361 xenografts (2.4-2.9 %ID/g [percentage injected dose per gram] for 111 In-NLS-trastuzumab and 1.1 %ID/g for 111 In-trastuzumab). 111 In-NLS-trastuzumab was 5-and 2-fold more potent at killing SK-BR-3 and MDA-MB-361 cells than 111 In-trastuzumab, respectively, whereas toxicity toward MDA-MB-231 cells was minimal. 111 In-NLS-trastuzumab was 6-fold more effective at killing SK-BR-3 cells than unlabeled trastuzumab. The development of recombinant antibodies for cancer therapy has emerged as one of the most promising areas in oncology (1). Trastuzumab (Herceptin; Hoffmann-La Roche), in particular, is a humanized monoclonal antibody (mAb) directed against the human epidermal growth factor receptor-2 (HER2/neu), a transmembrane receptor tyrosine kinase that is overexpressed in 25%-30% of breast cancers (BCs) and distant metastases (2). Trastuzumab shows clinical activity in women with HER2/neu-overexpressing metastatic BC and exhibits synergistic antitumor effects when combined with paclitaxel or anthracyclines, achieving overall response rates of 40%-60% (2). Despite its effectiveness in combination regimens, the response rate...

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Section: Discussionmentioning

confidence: 99%

111In-Labeled Trastuzumab (Herceptin) Modified with Nuclear Localization Sequences (NLS): An Auger Electron-Emitting Radiotherapeutic Agent for HER2/neu-Amplified Breast Cancer

Costantini¹,

Chan²,

Cai³

et al. 2007

Journal of Nuclear Medicine

166

176

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“…To trace the distribution of PspA after intranasal immunization, PspA was labeled with indium chloride (Nihon Medi-Physics, Tokyo, Japan) anhydride (Dojindo, Kumamoto, Japan) via N-terminal and ε-Lys amino groups, using diethylenetriaminepentaacetic acid as described previously (42). 111 In-labeled PspA was administered alone or as a complex with cCHP nanogel.…”

Section: Methodsmentioning

confidence: 99%

Nanogel-Based PspA Intranasal Vaccine Prevents Invasive Disease and Nasal Colonization by Streptococcus pneumoniae

et al. 2013

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kTo establish a safer and more effective vaccine against pneumococcal respiratory infections, current knowledge regarding the antigens common among pneumococcal strains and improvements to the system for delivering these antigens across the mucosal barrier must be integrated. We developed a pneumococcal vaccine that combines the advantages of pneumococcal surface protein A (PspA) with a nontoxic intranasal vaccine delivery system based on a nanometer-sized hydrogel (nanogel) consisting of a cationic cholesteryl group-bearing pullulan (cCHP). The efficacy of the nanogel-based PspA nasal vaccine (cCHP-PspA) was tested in murine pneumococcal airway infection models. Intranasal vaccination with cCHP-PspA provided protective immunity against lethal challenge with Streptococcus pneumoniae Xen10, reduced colonization and invasion by bacteria in the upper and lower respiratory tracts, and induced systemic and nasal mucosal Th17 responses, high levels of PspA-specific serum immunoglobulin G (IgG), and nasal and bronchial IgA antibody responses. Moreover, there was no sign of PspA delivery by nanogel to either the olfactory bulbs or the central nervous system after intranasal administration. These results demonstrate the effectiveness and safety of the nanogel-based PspA nasal vaccine system as a universal mucosal vaccine against pneumococcal respiratory infection.

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“…The radioactive peak that eluted at 13.5 min was collected, diluted with 30 ml H 2 O, and passed through a Sep-Pak C18 cartridge (Nihon Waters K.K., Tokyo, Japan). The In], half-life 2.805 d; Nihon Medi-Physics, Tokyo, Japan) anhydride (Dojindo, Kumamoto, Japan) via N-terminal and ε-Lys amino groups using DTPA as described previously (19 In]-cholera toxin were 638,000-915,000 (average, 775,000 cpm/mg protein; n = 4) and 825,000-909,000 cpm/mg protein (average, 867,000 cpm/mg protein; n = 2), respectively.…”

Section: Preparation Of Botulinum Mucosal Vaccine (Bohc/a)mentioning

confidence: 99%

In Vivo Molecular Imaging Analysis of a Nasal Vaccine That Induces Protective Immunity against Botulism in Nonhuman Primates

Yuki

Nochi

Harada

et al. 2010

The Journal of Immunology

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In vitrocytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2

Cited by 19 publications

References 26 publications

111In-Labeled Trastuzumab (Herceptin) Modified with Nuclear Localization Sequences (NLS): An Auger Electron-Emitting Radiotherapeutic Agent for HER2/neu-Amplified Breast Cancer

111In-Labeled Trastuzumab (Herceptin) Modified with Nuclear Localization Sequences (NLS): An Auger Electron-Emitting Radiotherapeutic Agent for HER2/neu-Amplified Breast Cancer

Nanogel-Based PspA Intranasal Vaccine Prevents Invasive Disease and Nasal Colonization by Streptococcus pneumoniae

In Vivo Molecular Imaging Analysis of a Nasal Vaccine That Induces Protective Immunity against Botulism in Nonhuman Primates

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