Radioiodinated apotransferrin for use in tumor diagnosis, imagin

Details Radioiodinated apotransferrin for use in tumor diagnosis, imagin Radioiodinated apotransferrin for use in tumor diagnosis, imagin

1987-04-01

1990-01-23

Maples, John S.

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

530394, 530402, A61K 4902, A61K 3704, A61K 3514, C07K 1514

Patent

active

048957143

DESCRIPTION:

BRIEF SUMMARY
This invention relates to protein conjugates for use in tumour diagnosis, imaging, localization or treatment.
Transferrin is a protein which occurs in blood plasma, including human blood plasma, and which has an important function in the transport of iron. The role of transferring and transferrin receptors on reticulocytes has been widely studied.
It has been noted recently that transferrin receptors are to be found on the surface of leukemia and lymphoma cells (Yeh, Taylor and Faulk, Vox Sanguinis, 1984, Vol. 46, page 217). It has been suggested that research into breast cancer diagnosis and therapy might be approached through the use of transferrin labelled with cytotoxic agents (Faulk et al, The Lancet, Aug. 23, 1980, page 392).
A favoured approach to producing tumor imaging agents has involved the linking of radioactive isotopes such as .sup.125 I to antibodies against tumour-associated surface antigens. The ability of such complexes to localise malignant cells selectively has, so far, been limited. An alternative, and more recent approach has been to use nuclear magnetic resonance, but this approach requires very expensive equipment. Another new approach is positron emission tomography.
Following the identification of transferrin receptors on the surface of tumour cells by Faulk and Galbraith (Proc. Roy. Soc. (B) 204: 83-97, 1979), Trowbridge and Domingo (Nature, Vol. 294, page 171, 1981) have obtained monoclonal antibodies against the transferrin receptor of human cells, and have coupled such antibodies to ricin or diphtheria toxin sub-units. They found that the antibody bound to human tumour cells as evidenced by the inhibition of cell growth in vitro caused by such conjugates. However, in experiments designed to test the effectiveness of the antibody-toxin conjugates in vivo, they found that anti-transferrin receptor antibody alone inhibits the growth of human melanoma cells in nude mice. They found no evidence that the conjugate is more effective than unmodified antibody in inhibiting growth of M21 melanoma cells in nude mice. That is to say, the cytotoxic properties of the ricin A moiety of the antibody-toxin conjugate were not manifest in vivo. It is essential that convincing in vivo data be put forward to support new methods of tumor diagnosis, localization, imaging or treatment.
Further teaching regardng such monoclonal antibodies can be found in US-A-No. 4434156.
In contrast to the results of Trowbridge and Domingo, it has been found that when an anti-tumour agent is conjugated with transferrin, not only does the protein moiety retain its affinity for transferrin receptors, but, moreover, the anti-tumor agent retains its anti-tumour properties (Yeh and Faulk, Clin. Imm. Immunopath., 1984, Vol. 32, pages 1-11). In this connection the reader is referred also to GB-B-2116979, to WO85/00812, and to EP-A-0134320.
Preparation of .sup.113 In-transferrin aggregates is described in DE-A-2108528, in DE-A-2150000 and in US-A-No. 3939258. .sup.103 Ru-labelled transferrin is disclosed in US-A-No. 4448762. A complex of radioactive gallium and transferrin is proposed as a component of a radiopharmaceutical composition in claim 20 of US-A-No. 4448763. In such aggregates the complexes and metal atom is chelated by the transferrin molecule.
Although such aggregates and complexes are proposed for use in radiodiagnosis, the radioactive metal is generally relatively loosely bound in the complex or aggregate by the chelating action of the protein and can be released from the complex or aggregate in vivo into the bloodstream. Hence the desired specificity of binding may be less than optimal and the presence of the free metal ions in the bloodstream may give rise to undesirable side effects.
Binding of .sup.125 I-transferrin to purified human transferrin receptor is mentioned in US-A-No. 4332785 but no description is given of its method of preparation.
A product which is designated as "Transferrin, human [.sup.125 I]" is listed under the reference NEX-212 in the 1985/1986 Research Products catalogue of New England N

REFERENCES:
patent: 3939258 (1976-02-01), Niemann
patent: 4332785 (1982-06-01), Allen et al.
patent: 4434156 (1984-02-01), Trowbridge
patent: 4447547 (1984-05-01), Allen et al.
patent: 4448762 (1984-05-01), Richards et al.
Aulbert et al, "Uptake of .sup.131 I-Transferrin in Tumor and Liver Tissue", Naturwissenschaften, 1981, 68(4), 212-213, [Chemical Abstracts, vol. 94, 188087y, p. 282, 1981].
Rostock et al., "Distribution of Transferrin and Localization of I-131-Labeled Antitransferrin", J. Nutr. Growth Cancer, 1985, 2(2), 71-74, [Chem. Abst., vol. 105, p. 293 205471, 1986].

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