Preparation of a biologically stable and immunogenically competent astatinated protein

Friedman, Alan M.; Zalutsky, Michael R.; Wung, Wally E.; Buckingham, F; Harper, Pauline; Scherr, George H.; Warner, Barbara B.; Hunter, Robert L.; Appelman, Evan H.; Rothberg, Richard M.; Fitch, Frank W.; Stuart, F. P.; Simonian, Simon J.

doi:10.1016/0047-0740(77)90146-2

Cited by 59 publications

(18 citation statements)

References 6 publications

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“…Trapping of the 211 At after volatilization from the cyclotron target has been accomplished using silica columns [31], bubbler traps [32], and capillary tubing cryotraps [30]. A problem in the past with dry distillation procedures for isolating 211 At from cyclotron targets is the wide variation in distillation yield from run to run.…”

Section: Recovery Of 211at From the Cyclotron Targetmentioning

confidence: 99%

Astatine-211: Production and Availability

Zalutsky

Pruszyński²

2011

CRP

154

117

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The 7.2-h half life radiohalogen 211At offers many potential advantages for targeted α-particle therapy; however, its use for this purpose is constrained by its limited availability. Astatine-211 can be produced in reasonable yield from natural bismuth targets via the 209Bi( α,2n)211At nuclear reaction utilizing straightforward methods. There is some debate as to the best incident α-particle energy for maximizing 211At production while minimizing production of 210At, which is problematic because of its 138.4-day half life α-particle emitting daughter, 210Po. The intrinsic cost for producing 211At is reasonably modest and comparable to that of commercially available 123I. The major impediment to 211At availability is attributed to the need for a medium energy α-particle beam for its production. On the other hand, there are about 30 cyclotrons in the world that have the beam characteristics required for 211At production.

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Section: Recovery Of 211at From the Cyclotron Targetmentioning

confidence: 99%

Astatine-211: Production and Availability

Zalutsky

Pruszyński²

2011

CRP

154

117

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“…Animal studies of bovine serum albumin labeled with this method indicated a low uptake of 211 At in the stomach, thyroid, spleen, and intestine compared to free 211 At in mice. 73 This methodology was improved and simplified by Zalutsky and Narula 74 with the development of an aromatic organotin precursor bearing an activated ester as the conjugation moiety. With a precursor activated for conjugation, this time-saving and more efficient procedure became a standard for radiolabeling proteins with radiolabeling of various antibodies in *2 hours in sufficient yields to support production of clinical trial doses (Fig.…”

Section: Astatination and Stability Of Biomolecules Of Interestmentioning

confidence: 99%

Production of [²¹¹At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy

Guérard

Gestin

Brechbiel

2013

Cancer Biotherapy and Radiopharmaceuticals

105

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(211)At is a promising radionuclide for α-particle therapy of cancers. Its physical characteristics make this radionuclide particularly interesting to consider when bound to cancer-targeting biomolecules for the treatment of microscopic tumors. (211)At is produced by cyclotron irradiation of (209)Bi with α-particles accelerated at ~28 MeV and can be obtained in high radionuclidic purity after isolation from the target. Its chemistry resembles iodine, but there is also a tendency to behave as a metalloid. However, the chemical behavior of astatine has not yet been clearly established, primarily due to the lack of any stable isotopes of this element, which precludes the use of conventional analytical techniques for its characterization. There are also only a limited number of research centers that have been able to produce this element in sufficient amounts to carry out extensive investigations. Despite these difficulties, chemical reactions typically used with iodine can be performed, and a number of biomolecules of interest have been labeled with (211)At. However, most of these compounds exhibit unacceptable instability in vivo due to the weakness of the astatine-biomolecule bond. Nonetheless, several compounds have shown high potential for the treatment of cancers in vitro and in several animal models, thus providing a promising basis that has allowed initiation of the first two clinical studies.

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“…While the authors were able to astatinate several imidazole derivatives from mercury precursors, they were found to be unstable under the oxidizing conditions needed for protein labeling. This necessitated the development of conjugation labeling methods and one of the first methods developed was labeling proteins by reacting with preformed [ 211 At]astatobenzoic acid, which was derived from a diazonium precursor [130-133]. The labeled acid was activated by converting it to the isobutyrl anhydride derivative and coupled subsequently to the protein.…”

Section: Antibodies and Their Engineered Fragmentsmentioning

confidence: 99%

Astatine Radiopharmaceuticals: Prospects and Problems

Vaidyanathan¹,

Zalutsky²

2008

CRP

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For the treatment of minimum residual diseases such micrometastases and residual tumor margins that remain after debulking of the primary tumor, targeted radiotherapy using radiopharmaceuticals tagged with α-particle-emitting radionuclides is very attractive. In addition to the their short range in tissue, which helps minimize harmful effects on adjacent normal tissues, α-particles, being high LET radiation, have several radiobiological advantages. The heavy halogen, astatine-211 is one of the prominent α-particle-emitting radionuclides in practice. Being a halogen, it can often be incorporated into biomolecules of interest by adapting radioiodination chemistry. A wide spectrum of compounds from the simple [ 211 At]astatide ion to small organic molecules, peptides, and large proteins labeled with 211 At have been investigated with at least two reaching the stage of clinical evaluation. The chemistry, cytotoxic advantages, biodistribution studies, and microdosimetry/ pharmacokinetic modeling of some of these agents will be reviewed. In addition, potential problems such as the harmful effect of radiolysis on the synthesis, lack of sufficient in vivo stability of astatinated compounds, and possible adverse effects when they are systemically administered will be discussed.

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Preparation of a biologically stable and immunogenically competent astatinated protein

Cited by 59 publications

References 6 publications

Astatine-211: Production and Availability

Astatine-211: Production and Availability

Production of [²¹¹At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy

Astatine Radiopharmaceuticals: Prospects and Problems

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Preparation of a biologically stable and immunogenically competent astatinated protein

Cited by 59 publications

References 6 publications

Astatine-211: Production and Availability

Astatine-211: Production and Availability

Production of [211At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy

Astatine Radiopharmaceuticals: Prospects and Problems

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Product

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About

Production of [²¹¹At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy