Preparation and evaluation of para-[211At]astatobenzoyl labeled anti-renal cell carcinoma antibody A6H F(ab′)2. In vivo distribution comparison with para-[125I]iodobenzoyl labeled A6H F(ab′)2

Wilbur, D. Scott; Vessella, Robert L.; Stray, James E.; Goffe, D.K.; Blouke, K.A.; Atcher, Robert W.

doi:10.1016/0969-8051(93)90092-9

Cited by 58 publications

(32 citation statements)

References 24 publications

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“…In most cases, the biodistribution of a protein radiolabeled with 125 I and 211 At are quite similar (11,15,16), but there have been previous reported exceptions (17,18), especially when smaller molecules, such as antibody fragments have been used. The results from these studies, with high uptake in stomach, lungs and spleen, indicate that free 211 At is released in vivo.…”

Section: Discussionmentioning

confidence: 95%

Biodistribution of 211At labeled HER-2 binding affibody molecules in mice

et al. 2007

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Abstract. The size of affibody molecules makes them suitable as targeting agents for targeted radiotherapy with the ·-emitter 211 At, since their biokinetic properties match the short physical half-live of 211 At. In this study, the potential for this approach was investigated in vivo. Two different HER-2 binding affibody molecules were radiolabeled with 211 At using both the linker PAB (N-succinimidyl-para-astatobenzoate) and a decaborate-based linker, and the biodistribution in tumorbearing nude mice was investigated. The influence of L-lysine and Na-thiocyanate on the 211 At uptake in normal tissues was also studied. Based on the biokinetic information obtained, the absorbed dose was calculated for different organs. Compared with a previous biodistribution with 125 I, the 211 At biodistribution using the PAB linker showed higher uptake in lungs, stomach, thyroid and salivary glands, indicating release of free 211 At. When the decaborate-based linker was used, the uptake in those organs was decreased, but instead, high uptake in kidneys and liver was found. The uptake, when using the PAB linker, could be significantly reduced in some organs by the use of L-lysine and/or Na-thiocyanate. In conclusion, affibody molecules have suitable blood-kinetics for targeted radionuclide therapy with 211 At. However, the labeling chemistry affects the distribution in normal organs to a high degree and needs to be improved to allow clinical use.

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Section: Discussionmentioning

confidence: 95%

Biodistribution of 211At labeled HER-2 binding affibody molecules in mice

et al. 2007

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“…211 At was produced by an α-particle irradiation (28 MeV) of natural bismuth, 209 Bi(α, 2n) 211 At, on a Scandatronix MC-50 cyclotron. The 211 At activity was distilled from the bismuth target at 650-700°C into a cooled trap as previously described (32). The dry distillation of 211 At was conducted in a charcoal filtered glove box (Innovative Technologies, radioisotope glove box).…”

Section: Radioactivitymentioning

confidence: 99%

Streptavidin in Antibody Pretargeting. 5. Chemical Modification of Recombinant Streptavidin for Labeling with the α-Particle-Emitting Radionuclides ²¹³Bi and ²¹¹At

et al. 2007

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We are investigating the use of recombinant streptavidin (rSAv) as a carrier molecule for the shortlived α-particle emitting radionuclides 213 Bi (t 1/2 = 45.6 min) and 211 At (t 1/2 = 7.21 h) in cancer therapy. To utilize rSAv as a carrier, it must be modified in a manner that permits rapid chelation or bonding with these short-lived radionuclides, and also modified in a manner that diminishes its natural propensity for localization in kidney. Modification for labeling with 213 Bi was accomplished by conjugation of rSAv with the DTPA derivative p-isothiocyanato-benzyl-CHX-A″ (CHX-A″), 3a. Modification for direct labeling with 211 At was accomplished by conjugation of rSAv with an isothiocyanatophenyl derivative of a nido-carborane (nCB), 3b, or an isothiocyanatophenyldPEG ™ /decaborate(2-) derivative, 3c. After conjugation of the chelating or bonding moiety, rSAv was further modified by reaction with an excess (50-100 equivalents) of succinic anhydride. Succinylation of the lysine amines has previously been shown to greatly diminish kidney localization. rSAv modified by conjugation with 3a and succinylated radiolabeled rapidly with 213 Bi (< 5 min), providing a 72% isolated yield. 211 At labeling of modified rSAv was accomplished in aqueous solution using chloramine-T as the oxidant. Astatination of rSAv conjugated with 3b and succinylated occurred very rapidly (<1 min), providing a 50% isolated radiochemical yield. Astatination of rSAv conjugated with 3c and succinylated was also very rapid (<1 min) providing 66-71% isolated radiochemical yields. Astatination of succinylated rSAv, 2a, which did not have conjugated borane cage moieties, resulted in much lower radiolabeling yield (18%). The 213 Bi-or 211 At-labeled modified rSAv preparations were mixed with the corresponding 125 I-labeled rSAv, and dual-label in vivo distributions were obtained in athymic mice. The in vivo data show that 213 Bi-labeled succinylated rSAv [ 213 Bi]6a has tissue concentrations similar to 125 I-labeled modified rSAv [ 125 I] 6b, suggesting that 213 Bi is quite stable towards release from the chelate in vivo. In vivo data also indicate that the 211 At-labeled rSAv conjugated with 3b or 3c and succinylated are stable to in vivo deastatination, whereas succinylated rSAv lacking a boron cage moiety is subject to some deastatination. The modified rSAv conjugated with nido-carborane derivative 3b has a higher retention in many tissues than rSAv without the carborane conjugated. Interestingly, the rSAv conjugated with 3c, which also contains a m-dPEG 12 ™ moiety, has significantly decreased concentrations in blood and other tissues when compared with direct labeled rSAv, suggesting that it may be a good candidate for further study. In conclusion, rSAv that has been modified with CHX-A″ and succinylated (i.e. 5a) may be useful as a carrier of 213 Bi. The encouraging results obtained with the PEGylated decaborate(2-) derivative 3c and succinylated (i.e. 5c) suggests that its further study as a carrier of 211 At in pretargeting prot...

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“…9 Therefore, a number of different bifunctional labeling reagents have been developed for the astatination of proteins. [10][11][12][13] The radiochemistry is generally conducted in two steps: labeling of the reagent and conjugation of the labeled reagent to the antibody. However, when using this strategy, problems generally occur with yields and the final quality under high-activity conditions due to radiolytic effects in the reacting solvent.…”

Section: Introductionmentioning

confidence: 99%

Shelf-Life of ɛ-Lysyl-3-(Trimethylstannyl)Benzamide Immunoconjugates, Precursors for ²¹¹At Labeling of Antibodies

Aneheim

Halleröd

Albertsson

et al. 2015

Cancer Biotherapy and Radiopharmaceuticals

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Astatine-211 is possibly the most promising radionuclide for targeted a-particle therapy when it comes to the treatment of occult disseminated cancer. Preclinical research has proven effective, and patient studies have been initiated based on these results. However, a lack of production capacity and the complex radiochemistry of 211 At are major obstacles for research and prospective clinical applications. In the present study, astatination of immunoconjugates, already prepared well in advance before radiolabeling, was performed to investigate the possibility of formulating a kit-like reagent for the production of 211 At radiopharmaceuticals. The shelf-life of e-lysyl-3-(trimethylstannyl)benzamide immunoconjugates was evaluated, that is, the effect of different storage times on the quality of the immunoconjugates. The quality being referred to is the capacity to maintain a good radiochemical yield and good cell-binding property after labeling with 211 At. The stability of the conjugates was found to be pH dependent with high stability at pH ‡ 7 and less stability at pH £ 5.5. The immunoconjugates (based on trastuzumab) could be kept for more than 3 months in a phosphate buffered saline solution (pH 7.4) at 4°C before labeling, without compromising the quality of the labeled product. The conjugates are also unaffected by storage at -20°C. Conjugates with a good shelf-life compatible with distant shipping as well as improved radiochemistry are important steps to facilitate further clinical progress with 211 At.

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Preparation and evaluation of para-[211At]astatobenzoyl labeled anti-renal cell carcinoma antibody A6H F(ab′)2. In vivo distribution comparison with para-[125I]iodobenzoyl labeled A6H F(ab′)2

Cited by 58 publications

References 24 publications

Biodistribution of 211At labeled HER-2 binding affibody molecules in mice

Biodistribution of 211At labeled HER-2 binding affibody molecules in mice

Streptavidin in Antibody Pretargeting. 5. Chemical Modification of Recombinant Streptavidin for Labeling with the α-Particle-Emitting Radionuclides ²¹³Bi and ²¹¹At

Shelf-Life of ɛ-Lysyl-3-(Trimethylstannyl)Benzamide Immunoconjugates, Precursors for ²¹¹At Labeling of Antibodies

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Preparation and evaluation of para-[211At]astatobenzoyl labeled anti-renal cell carcinoma antibody A6H F(ab′)2. In vivo distribution comparison with para-[125I]iodobenzoyl labeled A6H F(ab′)2

Cited by 58 publications

References 24 publications

Biodistribution of 211At labeled HER-2 binding affibody molecules in mice

Biodistribution of 211At labeled HER-2 binding affibody molecules in mice

Streptavidin in Antibody Pretargeting. 5. Chemical Modification of Recombinant Streptavidin for Labeling with the α-Particle-Emitting Radionuclides 213Bi and 211At

Shelf-Life of ɛ-Lysyl-3-(Trimethylstannyl)Benzamide Immunoconjugates, Precursors for 211At Labeling of Antibodies

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Streptavidin in Antibody Pretargeting. 5. Chemical Modification of Recombinant Streptavidin for Labeling with the α-Particle-Emitting Radionuclides ²¹³Bi and ²¹¹At

Shelf-Life of ɛ-Lysyl-3-(Trimethylstannyl)Benzamide Immunoconjugates, Precursors for ²¹¹At Labeling of Antibodies