Carrier‐free astatination of steroid hormones

Pillai, K. K.; McLaughlin, W. W.; R, Lambrecht; Bloomer, W. W.

doi:10.1002/jlcr.2580240913

Cited by 16 publications

(8 citation statements)

References 16 publications

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“…Antibody Biodistribution. 211At-labeled Mel-14 F(ab')2 levels in D-54 MG human glioma xenografts reached 11.0 ± 2.4% ID/g by 3 hr and were >12% ID/g until 24 hr, at which time they had decreased to 8.7 ± 2.1% ID/g (Fig. 2).…”

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confidence: 93%

“…Normal tissue doses for RPC 5 F(ab')2 were quite similar. todestannylation of tri-n-butylstannyl compounds in the absence of iodide carrier has been reported previously (15,24). The procedure described herein incorporates several significant modifications of our initial method for labeling proteins with 211At by means of m-BuATE.…”

mentioning

confidence: 99%

“…In the second, mice received 211At-labeled RPC 5 F(ab')2 (5 ,ug, 8 ,uCi) and "3'I-labeled F(ab')2 (4 ,ug, 5 ,uCi). Mice were euthanized by halothane overdose at 3, 5, 7, 14.5, and 24 hr, approximating the times at which the injected 2"'At had decayed to 75%, 60%, 50%, 25%, and 10% of initial levels. The biodistribution of 211At- (Fig.…”

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confidence: 99%

“…Similar tumor localization was observed in the second experiment when the mAb labels were reversed. In both studies, differences in tumor uptake were statistically significant (Student's t test; P < 0.01, 3 hr; P < 0.001, [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] hr). With Mel-14 F(ab')2, no significant differences were observed in tumor localization of 2"At and 131I until 24 hr, at which time the "3'1-labeled mAb exhibited higher uptake (12.8 Tumor/normal tissue ratios of 211At after injection of 211At-labeled Mel-14 F(ab')2 and control RPC 5 F(ab')2 are compared in Fig.…”

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confidence: 99%

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Labeling monoclonal antibodies and F(ab')2 fragments with the alpha-particle-emitting nuclide astatine-211: preservation of immunoreactivity and in vivo localizing capacity.

Zalutsky

Garg

Friedman

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

126

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a-Particles such as those emitted by 21'At may be advantageous for radioimmnunotherapy since they are radiation of high linear energy transfer, depositing high energy over a short distance. Here we describe a strategy for labeling monoclonal antibodies and F(ab')2 fragments with 211At by means of the bifunctional reagent N-succinimidyl 3-(trimethylstannyl)benzoate. An intact antibody, 81C6, and the F(ab')2 fragment of Mel-14 (both reactive with human gliomas) were labeled with 211At in high yield and with a specific activity of up to 4 mCi/mg in a time frame compatible with the 7.2-hr half-life of 211At. Quantitative in vivo binding assays demonstrated that radioastatination was accomplhed with maintenance of high specific binding and affinity. Comparison of the biodistribution of 211At-labeled Mel-14 F(ab')2 to that of a nonspecific antibody fragment labeled with 21'At and 131I in athymic mice bearing D-54 MG human glioma xenografts demonstrated selective and specific targeting of 211At-labeled antibody in this human tumor model. and in vivo (7,8). In order to ensure the formation of an aryl astatide bond, a method was developed for astatinating proteins via acylation withp-astatobenzoic acid (9). Although this approach has markedly increased the in vivo stability of 2"1At-labeled proteins, even after subsequent optimization (10) the radiochemical yield and specific activity (maximum of 1 astatine atom per 20,000 protein molecules) are inadequate to permit meaningful biological evaluation of the radiotherapeutic potential of 211At-labeled mAbs.This paper describes a method that utilizes N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE; ATE, "alkyltin ester") for labeling mAbs with 2lAt. An IgG2b immunoglobulin and an IgG2a F(ab')2 fragment were labeled with 211At in high yield and maintained immunoreactivity and affinity after astatination. Moreover, biodistribution studies in athymic mice bearing subcutaneous tumors indicated that selective tumor uptake of 211At can be achieved following administration of 211At-labeled mAbs.From a radiobiological perspective, nuclides that emit aparticles could offer advantages for certain radiotherapeutic applications. For example, 6-to 8-MeV a-particles (1 eV = 1.602 x 10-19 J) have a range in tissue of55-80 ,m, providing the potential for matching the cellular specificity of a monoclonal antibody (mAb) and radiation with cytotoxic effects limited to only a few cell diameters. These a-particles have a linear energy transfer (LET) of maximum relative biological effectiveness about 8 times that of 13-or y-radiation (1). The cytotoxic effects of high-LET radiations are thought to be irreparable (2), presumably due to the relatively high proportion of non-rejoining DNA strand breaks that they have been observed to induce in vitro (3). Since the cytotoxic effects of a-particles are nearly oxygen-independent (1), eradication of hypoxic tumor-cell populations also might be possible. IgG2a that does not bind to any known antigen. Methods for the production of F(ab')2 f...

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confidence: 93%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Labeling monoclonal antibodies and F(ab')2 fragments with the alpha-particle-emitting nuclide astatine-211: preservation of immunoreactivity and in vivo localizing capacity.

Zalutsky

Garg

Friedman

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

126

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“…We have reported the successful preparation of 17-alpha-211 At vinylestradiol ( 211 AtVE2) and 11-betamethoxy-17-alpha-211 At-vinylestradiol ( 2n AtMVE2) in high radiochemical yield under carrier-free conditions [3]. 17-alpha-E-tributylstannylvinylestradiol has been prepared by a single step procedure starting from 17-alphaethynylestradiol.…”

Section: Steroid Hormonesmentioning

confidence: 99%

Experimental Therapeutics Using Alpha Particles

Bloomer

McLaughlin

1989

Radiochimica Acta

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Because of their limited path length and the high LET nature of the emitted radiations, alpha emitters are particularly wellsuited for selective cell destruction if appropriate carrier molecules can be identified. Among the potential carriers for alpha emitters are steroid hormones and melanin precursors. The development of rapid stereo-specific labeling and separation procedures for astatine labeled radiopharmaceuticals will play a critical role in implementing these strategies.

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From Organometallic Compounds

Lee¹

1989

Inorganic Reactions and Methods

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Carrier‐free astatination of steroid hormones

Cited by 16 publications

References 16 publications

Labeling monoclonal antibodies and F(ab')2 fragments with the alpha-particle-emitting nuclide astatine-211: preservation of immunoreactivity and in vivo localizing capacity.

Labeling monoclonal antibodies and F(ab')2 fragments with the alpha-particle-emitting nuclide astatine-211: preservation of immunoreactivity and in vivo localizing capacity.

Experimental Therapeutics Using Alpha Particles

From Organometallic Compounds

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