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Michael Bouvet - One of the best experts on this subject based on the ideXlab platform.
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humanized anti tumor associated Glycoprotein 72 for submillimeter near infrared detection of colon cancer in metastatic mouse models
Journal of Surgical Research, 2020Co-Authors: Hannah M Hollandsworth, Siamak Amirfakhri, Filemoni Filemoni, Robert M Hoffman, Justin Molnar, Paul J Yazaki, Michael BouvetAbstract:Abstract Background Tumor-Associated Glycoprotein (TAG)–72 is a pancarcinoma antigen that is overexpressed in greater than 80% of colorectal adenocarcinomas. CC49 is a TAG-72–specific antibody. The aim of the present study was to demonstrate selective imaging of colon tumors and metastases with the humanized TAG-72 antibody (anti-huCC49) conjugated to a near-infrared fluorophore in orthotopic mouse models. Methods Anti-huCC49 was conjugated to near-infrared dye IR800CW. Mouse imaging was performed with the Pearl Trilogy Small Animal and FLARE Imaging Systems. Subcutaneous mouse models of colon cancer cell line LS174T were used to determine the optimal dose of administration and timing of imaging. Orthotopic mouse models of LS174T were established by surgical orthotopic implantation of LS174T tumors onto the serosa of the cecum. Peritoneal carcinomatosis models were established by injection of LS174T cells into the peritoneum of nude mice. Mice were administered anti-huCC49–IR800 via tail vein injection. Mice were euthanized 72 h later and imaged after laparotomy. Results Subcutaneous LS174T xenografts demonstrated optimal tumor detection 72 h after administration with 50 μg anti-huCC49-IR800CW. Tumors were visualized with fluorescence imaging with a mean tumor-to-liver ratio of 7.39 (standard deviation: 2.76). In the orthotopic model, metastases smaller than 1 mm were fluorescently visualized that were invisible with bright light. Conclusions Anti-huCC49–IR800CW provides sensitive and specific imaging of colon cancer and metastases at a submillimeter resolution in metastatic nude mice models. This provides a promising near-infrared probe for the imaging of colon cancer and metastases for preoperative diagnosis and fluorescence-guided surgery.
David Colcher - One of the best experts on this subject based on the ideXlab platform.
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Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells
Frontiers Media S.A., 2018Co-Authors: David Colcher, John P. Murad, Anna K. Kozlowska, Hee Jun Lee, Maya Ramamurthy, Wen-chung Chang, Paul Yazaki, John ShivelyAbstract:Impressive clinical efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy for hematological malignancies have prompted significant efforts in achieving similar responses in solid tumors. The lack of truly restricted and uniform expression of Tumor-Associated antigens, as well as limited T cell persistence and/or tumor trafficking pose major challenges for successful translation of CAR T cell therapy in solid tumors. Recent studies have demonstrated that aberrantly glycosylated cell surface proteins on tumor cells are amenable CAR targets. Tumor-Associated Glycoprotein 72 (TAG72) antigen is the sialyl-Tn found on multiple O-Glycoproteins expressed at high levels on the surface of several cancer types, including ovarian cancer. Here, we developed a humanized TAG72-specific CAR containing a 4-1BB intracellular co-stimulatory signaling domain (TAG72-BBζ). TAG72-BBζ CAR T cells showed potent antigen-dependent cytotoxicity and cytokine production against multiple TAG72+ ovarian cancer cell lines and patient-derived ovarian cancer ascites. Using in vivo xenograft models of peritoneal ovarian tumors, regional intraperitoneal delivery of TAG72-BBζ CAR T cells significantly reduced tumor growth, extended overall survival of mice, and was further improved with repeat infusions of CAR T cells. However, reduced TAG72 expression was observed in early recurring tumors, which coincided with a lack of T cell persistence. Taken together, we demonstrate efficacy with TAG72-CAR T cells in ovarian cancer, warranting further investigations as a CAR T cell therapeutic strategy for this disease
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Data_Sheet_1_Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells.PDF
2018Co-Authors: John P. Murad, David Colcher, Anna K. Kozlowska, Hee Jun Lee, Maya Ramamurthy, Wen-chung Chang, Paul Yazaki, John Shively, Mihaela Cristea, Stephen J. FormanAbstract:Impressive clinical efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy for hematological malignancies have prompted significant efforts in achieving similar responses in solid tumors. The lack of truly restricted and uniform expression of Tumor-Associated antigens, as well as limited T cell persistence and/or tumor trafficking pose major challenges for successful translation of CAR T cell therapy in solid tumors. Recent studies have demonstrated that aberrantly glycosylated cell surface proteins on tumor cells are amenable CAR targets. Tumor-Associated Glycoprotein 72 (TAG72) antigen is the sialyl-Tn found on multiple O-Glycoproteins expressed at high levels on the surface of several cancer types, including ovarian cancer. Here, we developed a humanized TAG72-specific CAR containing a 4-1BB intracellular co-stimulatory signaling domain (TAG72-BBζ). TAG72-BBζ CAR T cells showed potent antigen-dependent cytotoxicity and cytokine production against multiple TAG72+ ovarian cancer cell lines and patient-derived ovarian cancer ascites. Using in vivo xenograft models of peritoneal ovarian tumors, regional intraperitoneal delivery of TAG72-BBζ CAR T cells significantly reduced tumor growth, extended overall survival of mice, and was further improved with repeat infusions of CAR T cells. However, reduced TAG72 expression was observed in early recurring tumors, which coincided with a lack of T cell persistence. Taken together, we demonstrate efficacy with TAG72-CAR T cells in ovarian cancer, warranting further investigations as a CAR T cell therapeutic strategy for this disease.
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penetratin improves tumor retention of single chain antibodies a novel step toward optimization of radioimmunotherapy of solid tumors
Cancer Research, 2005Co-Authors: Maneesh Jain, Subhash C Chauhan, Ajay P Singh, Ganesh Venkatraman, David Colcher, Surinder K BatraAbstract:Single-chain Fv (scFv) antibody fragments exhibit improved pharmacokinetics and biodistribution compared with intact IgG. The tumor uptake of scFvs is rapid, and the serum half-life is shorter than IgG. However, scFvs exhibit lower net dose deposition in the tumor due to a shorter residence time that limits their use in radioimmunotherapy. To improve the tumor uptake and retention of scFvs, we investigated the utility of cell-penetrating peptides, penetratin and transactivator of transcription (TAT). Biodistribution studies were done in LS174T tumor-bearing mice with divalent scFv derived from anti-Tumor-Associated Glycoprotein 72 monoclonal antibody (mAb) CC49. Penetratin increased the tumor retention of scFvs without affecting the peak dose accumulation. The percentage of doses retained in tumors at 24 hours post-administration with a control (no peptide), penetratin, and TAT were 27.25%, 79.84%, and 48.55%, respectively, of that accumulated at 8 hours postinjection. The tumor-to-blood ratios at 24 hours postadministration were 7.14, 19.53, and 16.48 with control, penetratin, and TAT treatment, respectively, whereas the pharmacokinetics were unaltered. Coinjection with TAT, however, resulted in increased uptake of the radioconjugate by the lungs. Autoradiography of the excised tumors indicated a more homogenous distribution of the radiolabeled scFv with both penetratin and TAT in comparison with the control treatment. Real-time whole-body imaging of the live animals confirmed improved tumor localization with penetratin without any increase in the uptake by normal tissues. In conclusion, a significant improvement in the tumor retention of sc(Fv)2 was achieved by administration of penetratin. Therefore, the combination of penetratin and scFvs has the potential of improving the utility of mAb-based radiopharmaceuticals.
Daniel Rukavina - One of the best experts on this subject based on the ideXlab platform.
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tumor associated Glycoprotein tag 72 is a natural ligand for the c type lectin like domain that induces anti inflammatory orientation of early pregnancy decidual cd1a dendritic cells
Journal of Reproductive Immunology, 2011Co-Authors: Gordana Laskarin, Arnela Redzovic, Ivan Vlastelic, Herman Haller, Suzana Srsen Medancic, Graziella Solinas, Daniel RukavinaAbstract:Tumor-Associated Glycoprotein-72 (TAG-72) is physiologically present in secretory phase endometrium, but its presence and possible immunological role in early normal human pregnancy decidua has not received attention. The double labeling of paraffin-embedded early pregnancy decidua sections using B-72.4 anti-TAG-72 mAb and MNF 116 anti-cytokeratin mAb revealed the absence of TAG-72 in uterine decidua of normal and pathological pregnancies (non-embryonic pregnancy and missed abortion) at the implantation sites, although it was present in epithelial cells at and away from the tubal implantation site of an ectopic pregnancy. TAG-72 binds and internalizes by reacting with the mannose receptor (MR-CD206) or with DC-specific ICAM reacting non-integrin (DC-SIGN-CD209) on decidual CD1a+ cells. Decidual CD1a+ cells stimulated with TAG-72 decreased CD83 expression and diminished IL-15 and IFN-γ intracellular production. TAG-72-treated CD1a+ cells decreased IFN-γ production in syngenic decidual and allogenic cord blood T cells even in the presence of lipopolysaccharide. TAG-72- and lipopolysaccharide-pre-treated CD1a+ cells significantly increased IL-4 expression in allogenic cord blood T cells. TAG-72 increased allogenic cord blood T cell proliferation, mediated by decidual CD1a+ cells, compared with its effect on the proliferation of syngenic decidual T cells. All these data emphasize the anti-inflammatory properties of TAG-72-treated decidual CD1a+ cells in terms of their interaction with T cells. Thus, the absence of TAG-72 at the maternal-fetal interface during early pregnancy could lead to a mild pro-inflammatory response that may be beneficial for pregnancy success and trophoblast growth control.
Jeffrey Schlom - One of the best experts on this subject based on the ideXlab platform.
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generation and characterization of a single gene encoded single chain tetravalent antitumor antibody
Clinical Cancer Research, 1999Co-Authors: Ameurfina D Santos, Jeffrey Schlom, S. V. S. Kashmiri, Patricia Horan Hand, Eduardo A PadlanAbstract:Monoclonal antibody (mAb) CC49, a murine IgG1, reacts with the Tumor-Associated Glycoprotein-72 expressed on a variety of carcinomas. In clinical trials, radiolabeled CC49 has shown excellent tumor localization to a variety of carcinomas. To minimize the immunogenicity of CC49 mAb in patients, a humanized CC49 (HuCC49) was generated by complementarity-determining region (CDR) grafting. The relative affinity of HuCC49 was 2–3-fold less than that of the murine mAb. With the aim of improving tumor targeting, attempts have been made to enhance the avidity of the HuCC49 mAb. Previous research has yielded a single geneencoded immunoglobulin, SCIgcCC49ΔCH1, which is a dimer of a single chain consisting of CC49 single-chain Fv linked to the NH2 terminus of the human γ1 Fc through the hinge region. This molecule is comparable to the mouse-human chimeric CC49 in terms of in vitro antigen binding properties, cytolytic activity, and rate of plasma clearance in athymic mice bearing human tumor xenografts. Recently, a single gene encoding a single-chain immunoglobulin consisting of a HuCC49 diabody attached to human γ1 Fc via the hinge region was constructed. The diabody, a bivalent antigen-binding structure, is made up of variable heavy (VH)/variable light (VL) domains and VL/VH domains. In each of the variable domain pairs, the VH and VL domains are linked through a short linker peptide. Meanwhile, the two pairs are linked via a 30-residue Gly-Ser linker peptide to yield two antigen-binding sites by lateral and noncovalent association of the VL of one pair with the VH of the other. Transfectomas expressing the single-gene immunoglobulin secrete a homodimer of about M r 160,000 that reacts to Tumor-Associated Glycoprotein-72. This tetravalent humanized antitumor immunoglobulin molecule may potentially be an efficacious therapeutic and diagnostic reagent against a wide range of human carcinomas.
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microautoradiographic analysis of the normal organ distribution of radioiodinated single chain fv and other immunoglobulin forms
Cancer Research, 1993Co-Authors: Takashi Yokota, Diane E Milenic, Marc Whitlow, James F Wood, Steven L Hubert, Jeffrey SchlomAbstract:Abstract In previous studies, we have compared the immunochemical properties, the in vivo pharmacokinetics, and the tumor penetrance of a radioiodinated single-chain Fv (sFv) in comparison with other immunoglobulin (Ig) forms (intact IgG, F(ab′) 2 , and Fab′) (Cancer Res., 51: 6363–6371, 1991). Biodistribution studies demonstrated a higher percent injected dose/g in the liver and spleen for the intact IgG and F(ab′) 2 . Renal uptake was observed with the Fab′ and F(ab′) 2 , whereas the sFv demonstrated no specific localization in either of these organs. The 125 I-labeled sFv also demonstrated a more even distribution throughout the tumor xenografts as compared to the other Ig forms (Cancer Res., 52: 3402–3408, 1992). Subsequent studies utilizing the sFv conjugated with a radiometal ( 177 Lu) demonstrated that the sFv was being metabolized by the kidney, and a significantly higher percent injected dose/g was obtained with a 177 Lu-labeled sFv as compared to a 125 I-labeled sFv (Cancer Res., 52: 6413–6417, 1992). These previous studies indicated the potential utility of radioiodinated sFv and other Ig fragments for use in radioimmunoguided surgery with a hand-held probe, diagnostic imaging, and possibly therapy. The present study compares the distribution in normal tissues of the 4 Ig forms of monoclonal antibody (MAb) CC49, which is directed against a pancarcinoma antigen (Tumor-Associated Glycoprotein-72). 125 I-labeled sFv, Fab′, F(ab′) 2 , and IgG of MAb CC49 were administered to athymic mice either bearing or not bearing the Tumor-Associated Glycoprotein-72 positive human colon carcinoma xenograft (LS-174T). At various intervals following the i.v. injection of the Ig forms, the liver, spleen, kidneys, and lungs were removed for autoradiographic analyses. Dramatic differences were observed in the kidney; the IgG was found only in the renal vasculature, whereas the Fab′, F(ab′) 2 , and sFv showed a high density of grains in the cortical tubules. In the liver, the IgG and F(ab′) 2 were found in association with hepatocytes, Kupffer cells, and in the sinusoids; the Fab′ and sFv were primarily associated with the Kupffer cells. In the spleen, the Ig forms localized to the marginal zones surrounding the lymphoid follicles. No specific accumulation of grains for any of the Ig forms was observed in the lung. In each of the tissues, the clearance rates were related to the size of the Ig form. The localization in the liver and spleen was determined to be antigen-mediated. No specific localization was observed when 125 I-labeled BL-3, an isotype-matched control MAb, was injected into tumor-bearing mice, or, when the 125 I-labeled CC49 IgG was administered to non-tumor-bearing mice. By defining the interactions of a MAb and its modified forms not only with tumor lesions but also with normal organs and tissues, more rational protocols for uses of a MAb and its various forms, including sFv9s, can be designed for diagnostic and therapeutic applications.
Eduardo A Padlan - One of the best experts on this subject based on the ideXlab platform.
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generation and characterization of a single gene encoded single chain tetravalent antitumor antibody
Clinical Cancer Research, 1999Co-Authors: Ameurfina D Santos, Jeffrey Schlom, S. V. S. Kashmiri, Patricia Horan Hand, Eduardo A PadlanAbstract:Monoclonal antibody (mAb) CC49, a murine IgG1, reacts with the Tumor-Associated Glycoprotein-72 expressed on a variety of carcinomas. In clinical trials, radiolabeled CC49 has shown excellent tumor localization to a variety of carcinomas. To minimize the immunogenicity of CC49 mAb in patients, a humanized CC49 (HuCC49) was generated by complementarity-determining region (CDR) grafting. The relative affinity of HuCC49 was 2–3-fold less than that of the murine mAb. With the aim of improving tumor targeting, attempts have been made to enhance the avidity of the HuCC49 mAb. Previous research has yielded a single geneencoded immunoglobulin, SCIgcCC49ΔCH1, which is a dimer of a single chain consisting of CC49 single-chain Fv linked to the NH2 terminus of the human γ1 Fc through the hinge region. This molecule is comparable to the mouse-human chimeric CC49 in terms of in vitro antigen binding properties, cytolytic activity, and rate of plasma clearance in athymic mice bearing human tumor xenografts. Recently, a single gene encoding a single-chain immunoglobulin consisting of a HuCC49 diabody attached to human γ1 Fc via the hinge region was constructed. The diabody, a bivalent antigen-binding structure, is made up of variable heavy (VH)/variable light (VL) domains and VL/VH domains. In each of the variable domain pairs, the VH and VL domains are linked through a short linker peptide. Meanwhile, the two pairs are linked via a 30-residue Gly-Ser linker peptide to yield two antigen-binding sites by lateral and noncovalent association of the VL of one pair with the VH of the other. Transfectomas expressing the single-gene immunoglobulin secrete a homodimer of about M r 160,000 that reacts to Tumor-Associated Glycoprotein-72. This tetravalent humanized antitumor immunoglobulin molecule may potentially be an efficacious therapeutic and diagnostic reagent against a wide range of human carcinomas.
