Improved Targeting of Pancreatic Cancer

Karacay, Habibe; Goldenberg, David M.; Yeldell, Dion; Chang, Chien-Hsing; Modrak, David E.; Sharkey, Robert M.; Gold, David V.

doi:10.1158/1078-0432.ccr-03-0340

Cited by 29 publications

(22 citation statements)

References 58 publications

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“…19). Higher levels of TF10 in the blood would lead to unacceptably high binding of the radiolabeled peptide within the blood (i.e., low tumor/blood ratios), whereas administering the peptide at a later time would mean the concentration of TF10 in the tumor would be decreased with consequently reduced concentration of radiolabeled peptide within the tumor.…”

Section: Resultsmentioning

confidence: 99%

“…Production of DOTA-conjugated hPAM4, whole-IgG, has been described (7). In vitro characterization of the TF10, along with PAM4-IgG and other PAM4-based constructs, was conducted by enzyme immunoassay (4), SDS-PAGE (17), high-performance liquid chromatography (19), and lowpressure size-exclusion column chromatography (19).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, we have shown that pretargeting procedures can be used in combination with 99m Tc or 124 I for superior imaging capability over directly radiolabeled antibody fragments (17,18). Thus, a pretargeting system based on the specificity of PAM4 for pancreatic In-DTPA-peptide, as compared with directly radiolabeled PAM4 IgG (19). We now report the development of a novel recombinant, humanized bispecific monoclonal antibody (mAb), TF10, based on the targeting specificity of PAM4 to pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Bispecific, Trivalent Antibody Construct for Targeting Pancreatic Carcinoma

et al. 2008

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Preclinical and clinical studies have demonstrated the application of radiolabeled mAb-PAM4 for nuclear imaging and radioimmunotherapy of pancreatic carcinoma. We have now examined the ability of a novel PAM4-based, bispecific monoclonal antibody (mAb) construct, TF10, to pretarget a radiolabeled peptide for improved imaging and therapy. TF10 is a humanized, bispecific mAb, divalent for mAb-PAM4 and monovalent for mAb-679, reactive against the histaminesuccinyl-glycine hapten. Biodistribution studies and nuclear imaging of the radiolabeled TF10 and/or TF10-pretargeted hapten-peptide (IMP-288) were conducted in nude mice bearing CaPan1 human pancreatic cancer xenografts.125

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Novel Bispecific, Trivalent Antibody Construct for Targeting Pancreatic Carcinoma

et al. 2008

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“…131,132 PRIT approaches with PAM4, using a bivalent and, subsequently, a trivalent bispecific antibody that binds the HSG hapten (TF10), have recently demonstrated improved imaging abilities relative to conventional RIT. 133,134 The latter showed an approximately 200-fold improved tumor-to-blood ratio when compared with directly labeled PAM4 IgG antibody. 134 Given the flexibility of the HSG hapten, this system could be modified for therapeutic purposes, and radiation dose estimates suggested that PRIT with 90 Y-labeled TF10 would provide a greater antitumor effect than 90 Y-labeled PAM4.…”

Section: Figmentioning

confidence: 98%

Pretargeted Radioimmunotherapy for Hematologic and Other Malignancies

Walter

Press

Pagel

2010

Cancer Biotherapy and Radiopharmaceuticals

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SummationRadioimmunotherapy (RIT) has emerged as one of the most promising treatment options, particularly for hematologic malignancies. However, this approach has generally been limited by a suboptimal therapeutic index (target-to-nontarget ratio) and an inability to deliver sufficient radiation doses to tumors selectively. Pretargeted RIT (PRIT) circumvents these limitations by separating the targeting vehicle from the subsequently administered therapeutic radioisotope, which binds to the tumor-localized antibody or is quickly excreted if unbound. A growing number of preclinical proof-of-principle studies demonstrate that PRIT is feasible and safe and provides improved directed radionuclide delivery to malignant cells compared with conventional RIT while sparing normal cells from nonspecific radiotoxicity. Early phase clinical studies corroborate these preclinical findings and suggest better efficacy and lesser toxicities in patients with hematologic and other malignancies. With continued research, PRIT-based treatment strategies promise to become cornerstones to improved outcomes for cancer patients despite their complexities.

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“…We have examined bsMAb that can localize other tumor-associated antigens, such as colon-specific antigen-p (78), a MUC-1 antigen that is highly specific for pancreatic cancer (82), and CD20 for targeting non -Hodgkin's lymphoma (83). Studies have been initiated to examine the capability of an anti-CD20 Â anti-HSG bsMAb, prepared by the dock-and-lock method (63), to localize human lymphoma cells in SCID mice.…”

Section: Can Pretargeting Provide a New Paradigm For Antibody-based Mmentioning

confidence: 99%

Bispecific Antibody Pretargeting of Radionuclides for Immuno–Single-Photon Emission Computed Tomography and Immuno–Positron Emission Tomography Molecular Imaging: An Update

Sharkey

Karacay²,

McBride³

et al. 2007

Clinical Cancer Research

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Molecular imaging is intended to localize disease based on distinct molecular/functional characteristics. Much of today's interest in molecular imaging is attributed to the increased acceptance and role of 18F-flurodeoxyglucose (18F-FDG) imaging in a variety of tumors. The clinical acceptance of 18F-FDG has stimulated research for other positron emission tomography (PET) agents with improved specificity to aid in tumor detection and assessment. In this regard, a number of highly specific antibodies have been described for different cancers. Although scintigraphic imaging with antibodies in the past was helpful in patient management, most antibody-based imaging products have not been able to compete successfully with the sensitivity afforded by 18F-FDG-PET, especially when used in combination with computed tomography. Recently, however, significant advances have been made in reengineering antibodies to improve their targeting properties. Herein, we describe progress being made in using a bispecific antibody pretargeting method for immuno–single-photon emission computed tomography and immunoPET applications, as contrasted to directly radiolabeled antibodies. This approach not only significantly enhances tumor/nontumor ratios but also provides high signal intensity in the tumor, making it possible to visualize micrometastases of colonic cancer as small as 0.1 to 0.2 mm in diameter using an anti–carcinoembryonic antigen bispecific antibody, whereas FDG failed to localize these lesions in a nude mouse model. Early detection of micrometastatic non–Hodgkin's lymphoma is also possible using an anti-CD20–based bispecific antibody pretargeting procedure. Thus, this bispecific antibody pretargeting procedure may contribute to tumor detection and could also contribute to the detection of other diseases having distinct antigen targets and suitably specific antibodies.

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Improved Targeting of Pancreatic Cancer

Cited by 29 publications

References 58 publications

A Novel Bispecific, Trivalent Antibody Construct for Targeting Pancreatic Carcinoma

A Novel Bispecific, Trivalent Antibody Construct for Targeting Pancreatic Carcinoma

Pretargeted Radioimmunotherapy for Hematologic and Other Malignancies

Bispecific Antibody Pretargeting of Radionuclides for Immuno–Single-Photon Emission Computed Tomography and Immuno–Positron Emission Tomography Molecular Imaging: An Update

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