Pretargeting of Carcinoembryonic Antigen–Expressing Cancers with a Trivalent Bispecific Fusion Protein Produced in Myeloma Cells

et al. 2005

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Therapeutic Advantage of Pretargeted Radioimmunotherapy Using a Recombinant Bispecific Antibody in a Human Colon Cancer Xenograft

Karacay

Brard

et al. 2005

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“…Recombinant bispecific mAb are particularly attractive not only from the perspective of ease of production (only one cell line and one product need to be made) but also because their molecular size is approximately half the size as the conventionally used FabV Â FabV chemical conjugates, giving these constructs a distinct pharmacokinetic advantage (38). In addition, constructs can be prepared with divalent binding capability to the target tumor antigen and still be smaller in size than a FabV Â FabV bispecific mAb (38,39). Rossi et al (39) reported that this type of construct might have an advantage for pretargeting based on its higher uptake in tumors measured at a time when the blood concentration for this construct and a FabV Â FabV bispecific mAb were the same.…”

mentioning

confidence: 99%

“…In addition, constructs can be prepared with divalent binding capability to the target tumor antigen and still be smaller in size than a FabV Â FabV bispecific mAb (38,39). Rossi et al (39) reported that this type of construct might have an advantage for pretargeting based on its higher uptake in tumors measured at a time when the blood concentration for this construct and a FabV Â FabV bispecific mAb were the same. In preclinical and clinical practice, the bispecific mAb pretargeting methods have been used highly successfully without relying on a clearing step.…”

mentioning

confidence: 99%

Improving the Delivery of Radionuclides for Imaging and Therapy of Cancer Using Pretargeting Methods

Karacay

Cardillo

et al. 2005

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113

102

The article reviews the background and current status of pretargeting for cancer imaging and therapy with radionuclides. Pretargeting procedures were introduced f20 years ago as an alternative to directly radiolabeled antibodies. Because they were multistep processes, they were met with resistance but have since progressed to simple and improved procedures that could become the next generation of imaging and therapy with radionuclides. The separation of the radiolabeled compound from the antibody-targeting agent affords pretargeting procedures considerable flexibility in the radiolabeling process, providing opportunities for molecular imaging using g-or positron-emitting radionuclides and a variety of h-and a-emitting radionuclides of therapeutic applications. Pretargeting methods improve tumor/ nontumor ratios, exceeding that achieved with directly radiolabeled FabV fragments, particularly within just a few hours of the radionuclide injection. In addition, tumor uptake exceeds that of a FabV fragment by as much as 10-fold, giving pretargeting a greatly enhanced sensitivity for imaging. Advances in molecular biology have led to the development of novel binding proteins that have further improved radionuclide delivery in these systems. Studies in a variety of hematologic and solid tumor models have shown advantages of pretargeting compared with directly radiolabeled IgG for therapy, and there are several clinical studies under way that are also showing promising results. Thus, the next generation of targeting agents will likely employ pretargeting approaches to optimize radionuclide delivery for a wide range of applications.Radiation continues to play an integral role in the management of cancer, from the use of X-rays and computed tomography for detection to the use of external beam and interstitial radiotherapy (brachytherapy and rapid interstitial therapy) for treatment. Nuclear medicine, which involves the use of internally administered radionuclides, traditionally has played a minor role in the management of cancer, initially relying primarily on the use of [ 67 Ga]citrate for lymphoma imaging and 131 INa for thyroid cancer treatment. However, with the advent of positron emission tomography and [ 18 F]deoxyglucose, and thanks to the development of new antibody-guided therapeutics for non-Hodgkin's lymphoma and emerging peptide-targeted therapeutics, the role of nuclear medicine in the management of cancer is increasing (1, 2).Except for 131 INa and radionuclides used for palliation of bone pain that are selectively taken up by their respective tissues, the specificity for cancer of internally administered radionuclides depends on its coupling to a targeting compound. For example, [18 F]deoxyglucose is concentrated in cancers because they are more metabolically active than most other cells in the body and therefore will accrue more deoxyglucose than surrounding cells. Antibodies have been one of the most commonly used targeting agents, with an extensive history spanning over 50 years (3). During this...

“…Each construct has done exceptionally well in a pretargeting setting. We have focused on constructs with the ability to bind divalently to the tumor target antigen and monovalently to the hapten-peptide, because these constructs showed improved tumor uptake and retention of the radiolabeled hapten-peptide (64,77). The bsMAb pretargeting system of current interest is based on a unique hapten-binding system that provides greater flexibility for inserting haptenpeptides, with the capability of carrying a variety of different radionuclides (78).…”

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

Karacay²,

McBride³

et al. 2007

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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.