Pharmacokinetics and Clinical Evaluation of<sup>125</sup>I-Radiolabeled Humanized CC49 Monoclonal Antibody (HuCC49ΔC<sub>H</sub>2) in Recurrent and Metastatic Colorectal Cancer Patients

Xiao, Jim; Horst, Sara N.; Hinkle, George H.; Cao, Xianhua; Kocak, Ergun; Fang, Jing; Young, Donn C.; Khazaeli, M. B.; Agnese, Doreen M.; Sun, Duxin; Martin, Edward W.

doi:10.1089/cbr.2005.20.16

Cited by 26 publications

(31 citation statements)

References 26 publications

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“…Compared with murine CC49 antibody, the humanized antibody will overcome immunogenicity problem in clinical investigation and the deletion of C H 2 domain will decrease the size of nanoconjugates. Our previous studies25, 36 showed that HuCC49ΔCH2 could specifically bind to LS174T colon cancer cells which had overexpression of TAG-72. The in vitro binding studies by fluorescence microscopy, Prussian blue staining and MRI scan showed the specific targeting of the HuCC49ΔCH2 labeled SPIOs (MAb-SPIOs) in LS174T colon cancer cells in comparison with SPIOs and IgG-SPIOs.…”

Section: Discussionmentioning

confidence: 99%

Superparamagnetic Iron Oxide Nanotheranostics for Targeted Cancer Cell Imaging and pH-Dependent Intracellular Drug Release

et al. 2010

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Purpose-To develop antibody-and fluorescence-labeled superparamagnetic iron oxide nanoparticle (SPIO) "nanotheranostics" for magnetic resonance imaging (MRI) and fluorescence imaging of cancer cells and pH-dependent intracellular drug release.Method-SPIO nanoparticles (10 nm) were coated with amphiphilic polymers and PEGylated. The antibody HuCC49ΔCH2 and fluorescent dye 5-FAM were conjugated to the PEG of IONPs. Anticancer drugs doxorubicin (Dox), and azido-doxorubicin (Adox), MI-219, 17-DMAG containing primary amine, azide, secondary amine, and tertiary amine, respectively, were encapsulated into IONPs. The encapsulation efficiency and drug release at various pHs were determined using an LC-MS/MS. The cancer targeting and imaging were monitored using MRI and fluorescent microscopy in colon cancer cell line (LS174T). The pH-dependent drug release, intracellular distribution, and cytotoxicity were evaluated using microscopy and MTS assay.Results-The pegylation of SPIO and conjugation with antibody and 5-FAM increased SPIO size from 18 nm to 44 nm. Fluorescent imaging, magnetic resonance imaging (MRI) and Prussian blue staining demonstrated that HuCC49ΔCH2-SPIO increased cancer cell targeting. HuCC49ΔCH2-SPIO "nanotheranostics" decreased the T 2 values in MRI of LS174T cells from 117.3±1.8 ms to 55.5±2.6 ms. The loading capacities of Dox, Adox, MI-219, and 17-DMAG were 3.16 ± 0.77%, 6.04± 0.61%, 2.22± 0.42%, and 0.09±0.07%, respectively. Dox, MI-219 and 17-DMAG showed pH-dependent release while Adox didn't. Fluorescent imaging demonstrated the accumulation of HuCC49ΔCH2-SPIO "nanotheranostics" in endosomes/lysosomes. The encapsulated Dox was released in acidic lysosomes and diffused into cytosol and nuclei. In contrary, the encapsulated Adox only showed limited release in endosomes/lysosomes. HuCC49ΔCH2-SPIO "nanotheranostics" targetedly delivered more Dox to LS174T cells than nonspecific IgG-SPIO and resulted in a lower IC 50 (1.44 μM v.s. 0.44 μM).* To whom correspondence should be addressed: Duxin Sun, PhD, Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, MI 48109, duxins@umich Conclusion-The developed HuCC49ΔCH2-SPIO "nanotheranostics" provides an integrated platform for cancer cell imaging, targeted anticancer drug delivery and pH-dependently drug release.

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Section: Discussionmentioning

confidence: 99%

Superparamagnetic Iron Oxide Nanotheranostics for Targeted Cancer Cell Imaging and pH-Dependent Intracellular Drug Release

et al. 2010

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“…[106] For example, the murine anti-TAG-72 mAb (CC49) used in a phase I clinical trial for ovarian cancer induced human anti-mouse-antibody response [107]. However, another pilot clinical trial demonstrated that the humanized anti-TAG-72 antibody did not induce any immunogenic response, and the antibody is suitable for tumor targeting in human patients with high specificity and affinity [108]. Moreover, the same group demonstrated that this anti-TAG-72 humanized antibody (HuCC49ΔCH2) conjugated β-galactosidase selectively activated the geldanamycin prodrug (17-AG-C2_Gal).…”

Section: Enzyme Activated Prodrugmentioning

confidence: 99%

Prodrugs for improving tumor targetability and efficiency

Mahato

Tai

Cheng

2011

Advanced Drug Delivery Reviews

301

210

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As the mainstay in the treatment of various cancers for several decades, chemotherapy is successful but still faces challenges including non-selectivity and high toxicity. Improving the selectivity is therefore a critical step to improve the therapeutic efficacy of chemotherapy. Prodrug is one of the most promising approaches to increase the selectivity and efficacy of a chemotherapy drug. The classical prodrug approach is to improve the pharmaceutical properties (solubility, stability, permeability, irritation, distribution, etc.) via a simple chemical modification. This review will focus on various targeted prodrug designs that have been developed to increase the selectivity of chemotherapy drugs. Various tumor-targeting ligands, transporter-associated ligands, and polymers can be incorporated in a prodrug to enhance the tumor uptake. Prodrugs can also be activated by enzymes that are specifically expressed at a higher level in tumors, leading to a selective anti-tumor effect. This can be achieved by conjugating the enzyme to a tumor-specific antibody, or delivering a vector expressing the enzyme into tumor cells.

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“…Anti-TAG-72 monoclonal antibodies have been studied in preclinical animal models as well as in humans for cancer detection based on their high specificity against cancer antigens in various solid cancers 2. As previously reported, we have utilized monoclonal antibodies against TAG-72 for tumor detection in radioimmunoguided surgery (RIGS) 3–7. Historically, RIGS combined radioactive-labeled (i.e., I 125 ) monoclonal antibodies and a handheld gamma probe for the intraoperative detection and resection of tumor-bearing tissues in colorectal cancer patients 5.…”

Section: Introductionmentioning

confidence: 99%

Near-Infrared Fluorescence Labeled Anti-TAG-72 Monoclonal Antibodies for Tumor Imaging in Colorectal Cancer Xenograft Mice

Zou

Povoski

et al. 2009

Mol. Pharmaceutics

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Anti-TAG-72 monoclonal antibodies target the tumor-associated glycoprotein (TAG)-72 in various solid tumors. This study evaluated the use of anti-TAG-72 monoclonal antibodies, both murine CC49 and humanized CC49 (HuCC49ΔC H 2), for near-infrared fluorescent (NIR) tumor imaging in colorectal cancer xenograft models. The murine CC49 and HuCC49ΔC H 2 were conjugated with Cy7 monofunctional N-hydroxysuccinimide ester (Cy7-NHS). Both in vitro and in vivo anti-TAG-72 antibody binding studies were performed. The in vitro study utilized the human colon adenocarcinoma cell line LS174T that was incubated with Cy7, antibody-Cy7 conjugates, or excessive murine CC49 followed by the antibody-Cy7 conjugates and was imaged by fluorescence microscopy. The in vivo study utilized xenograft mice, bearing LS174T subcutaneous tumor implants, that received tail vein injections of Cy7, murine CC49-Cy7, HuCC49ΔC H 2-Cy7, or nonspecific IgG-Cy7 and were imaged by the Xenogen IVIS 100 system from 15 minutes to 288 hours. The biodistribution of the fluorescence labeled antibodies was determined by imaging the dissected tissues. The in vitro study revealed that the antibody-Cy7 conjugates bound to LS174T cells and were blocked by excessive murine CC49. The in vivo study demonstrated that murine CC49 achieved a tumor/blood ratio of 15 at 96 hours post-injection. In comparison, HuCC49ΔC H 2-Cy7 cleared much faster than murine CC49-Cy7 from the xenograft mice, and HuCC49ΔC H 2-Cy7 achieved a tumor/ blood ratio of 12 at 18 hours post-injection. In contrast, Cy7 and Cy7 labeled non-specific IgG resulted in no demonstrable tumor accumulation. When mice were injected with excessive unlabeled murine CC49 at 6 hours before the injection of murine CC49-Cy7 or HuCC49ΔC H 2-Cy7, both the intensity and retention time of the fluorescence from the tumor was reduced. In summary, the Cy7 labeled murine CC49 and HuCC49ΔC H 2 demonstrate tumor-targeting capabilities in living colorectal cancer xenograft mice and provide an alternative modality for tumor imaging.

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Pharmacokinetics and Clinical Evaluation of¹²⁵I-Radiolabeled Humanized CC49 Monoclonal Antibody (HuCC49ΔC_H2) in Recurrent and Metastatic Colorectal Cancer Patients

Abstract: C(H)2 region deletion of HuCC49DeltaC(H)2 MAb did not alter the pharmacokinetics compared to murine CC49. The favorable partition coefficient K of HuCC49DeltaC(H)2 MAb into tumors supports its use in RIGS.

Cited by 26 publications

References 26 publications

Superparamagnetic Iron Oxide Nanotheranostics for Targeted Cancer Cell Imaging and pH-Dependent Intracellular Drug Release

Superparamagnetic Iron Oxide Nanotheranostics for Targeted Cancer Cell Imaging and pH-Dependent Intracellular Drug Release

Prodrugs for improving tumor targetability and efficiency

Near-Infrared Fluorescence Labeled Anti-TAG-72 Monoclonal Antibodies for Tumor Imaging in Colorectal Cancer Xenograft Mice

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Pharmacokinetics and Clinical Evaluation of125I-Radiolabeled Humanized CC49 Monoclonal Antibody (HuCC49ΔCH2) in Recurrent and Metastatic Colorectal Cancer Patients

Abstract: C(H)2 region deletion of HuCC49DeltaC(H)2 MAb did not alter the pharmacokinetics compared to murine CC49. The favorable partition coefficient K of HuCC49DeltaC(H)2 MAb into tumors supports its use in RIGS.

Cited by 26 publications

References 26 publications

Superparamagnetic Iron Oxide Nanotheranostics for Targeted Cancer Cell Imaging and pH-Dependent Intracellular Drug Release

Superparamagnetic Iron Oxide Nanotheranostics for Targeted Cancer Cell Imaging and pH-Dependent Intracellular Drug Release

Prodrugs for improving tumor targetability and efficiency

Near-Infrared Fluorescence Labeled Anti-TAG-72 Monoclonal Antibodies for Tumor Imaging in Colorectal Cancer Xenograft Mice

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Product

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Pharmacokinetics and Clinical Evaluation of¹²⁵I-Radiolabeled Humanized CC49 Monoclonal Antibody (HuCC49ΔC_H2) in Recurrent and Metastatic Colorectal Cancer Patients