A pilot study of131I monoclonal antibodies in the therapy of leptomeningeal tumors

Ls, Lashford; Ag, Davies; Rb, Richardson; Sp, Bourne; Ja, Bullimore; Eckert, H; Jt, Kemshead; Coakham, Hb

doi:10.1002/1097-0142(19880301)61:5<857::aid-cncr2820610502>3.0.co;2-s

Cited by 102 publications

(22 citation statements)

References 19 publications

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“…It is envisioned, however, that the half-life and radiation properties of 211At might be most effectively exploited in clinical settings favorable for compartmental delivery, such as intrathecal administration for leptomenningeal neoplastic disease and intraperitoneal administration for neoplastic ascites of ovarian carcinoma. Intracompartmental delivery has been shown to increase the rate of tumor uptake of labeled mAbs and decrease the dose to normal tissues (40,41).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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 further way to approach the problems of the physiologic barriers encountered in tumors replaces commonly used systemic administrations with regional or compartmental delivery. Compartmental therapies with the mAbs that have been investigated include intraperitoneal injection, direct injection into cyst cavities within tumors, and intrathecal injection for the treatment of neoplastic meningitis (19,20). Instilling mAbs directly into the intrathecal space can limit systemic exposure of noncentral nervous system tissues that share antigens with tumors targeted by the mAbs.…”

Section: Discussionmentioning

confidence: 99%

Intrathecal administration of single-chain immunotoxin, LMB-7 [B3(Fv)-PE38], produces cures of carcinomatous meningitis in a rat model.

Pastan

Archer

McLendon

et al. 1995

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

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LMB-7 [B3(Fv)-PE38] is a single-chain immunotoxin constructed from the murine monoclonal antibody B3 and a truncated form of Pseudomonas exotoxin PE38. Antibody B3 recognizes a carbohydrate epitope found on solid tumors that frequently invade the intrathecal space and cause neoplastic meningitis. We tested the therapeutic value of intrathecally administered LMB-7 by using a model of human neoplastic meningitis in athymic rats. This model is representative of a clinical situation in that antibody B3 crossreacts with a number of normal tissues that can be used to monitor potential systemic toxicity. Treatment was begun 3 days after A431 tumor implantation. Without treatment, the animals median survival was 10 days. Intrathecal administration of 10 ,ug ofLMB-7 in 40 ,Il on days 3,5, and 7 produced 4 of 10 and 8 of 10 long-term survivors (>170 days) in two experiments. Of the long-term survivors, 2 of 4 and 7 of 8 survivors had no microscopic evidence of tumor and were considered histologic cures. Lack of significant toxicity in the effective dose range and specificity make LMB-7 an excellent candidate for intrathecal treatment of neoplastic meningitis in humans.At one time neoplastic meningitis was thought to be a rare complication, but with improvements in systemic cancer treatment and an increased awareness of intrathecal complications, an increase in the number of cases of neoplastic meningitis has been seen. The intrathecal compartment provides a reservoir for tumor growth, most likely due to a failure of systematically administered chemotherapeutic agents to reach a therapeutic level in the cerebrospinal fluid (1). To overcome systemic delivery limitations, direct infusion into the intrathecal space has been used.Monoclonal antibodies (mAbs) conjugated to specific radionuclides, drugs, and toxins are being actively investigated as therapeutic agents in the compartmental treatment of neoplastic meningitis. Immunotoxins are particularly appealing because they are not affected by tumor cell hypoxia as are some radiolabeled mAbs, and they are more efficient than mAbdrug conjugates (2). We have observed significant increases in survival by using a model of human neoplastic meningitis in athymic rats, in animals treated with LMB-1, an immunotoxin constructed with the intact IgG of mAb B3 and a truncated form of Pseudomonas exotoxin (D.D.B., G.E.A., R.E.M., H.S.F., H.E.F., L.H.P., J.H., and I.H.P., unpublished data). mAb B3 was chosen for this study because it reacts with many types of solid tumors including carcinomas of the colon, breast, lung, ovary, bladder, and stomach (3). Recombinant produced complete regression of large subcutaneous tumors arising from A431 epidermoid carcinoma cells and MCF-7 breast carcinoma cells. By using a human neoplastic meningitis model, we have now tested the therapeutic efficacy of this single-chain immunotoxin LMB-7. The nude rat is an excellent experimental model for this purpose because human cancer cells grow and produce meningitis and because some normal rat tissues ...

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“…These observations led us and others (Lashford et al, 1988;Epenetos et al, 1987) to investigate the role of radiolabelled monoclonal antibodies in the treatment of intracavity extensions of tumour. The intrathecal compartment appears particularly amenable to this approach for three reasons.…”

mentioning

confidence: 96%

Intrathecal administration of 131I radiolabelled monoclonal antibody as a treatment for neoplastic meningitis

Moseley

Ag²,

Rb³

et al. 1990

Br J Cancer

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A pilot study of131I monoclonal antibodies in the therapy of leptomeningeal tumors

Cited by 102 publications

References 19 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.

Intrathecal administration of single-chain immunotoxin, LMB-7 [B3(Fv)-PE38], produces cures of carcinomatous meningitis in a rat model.

Intrathecal administration of 131I radiolabelled monoclonal antibody as a treatment for neoplastic meningitis

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