astatine and Osteosarcoma

To determine the effects of 211At-labelled antibodies in solid tumour tissue, nude mice carrying OHS human osteosarcoma xenografts received intratumour injections at dosages of 1, 2 or 4 MBq (-1) tumour. The radioisotope was conjugated to either the osteosarcoma-specific monoclonal antibody TP-3 or the non-specific polyclonal antibody hlgGkappa. Tumour retention of injected radioimmunoconjugate (RIC), measured as the percentage of injected activity dosage per gram, was significantly higher for the [211At]TP-3 (203 +/- 93 at 24.1 h post injection) compared with the [211At]hlgGkappa (57 +/- 22 at 23.2 h post injection). The radioactive count rates in body (measured at neck and abdomen) were significantly lower with the TP-3 than with the hlgGkappa. Microautoradiography of the tumour radionuclide distribution was different for the two RICs, i.e. the [211At]TP-3 was to a larger extent concentrated near the injection site, whereas the [211At]hlgGkappa was more evenly distributed all over the tumour. The tumour growth was significantly delayed as a function of the injected activity dosage but without significant difference between the specific and the non-specific RIC. According to this study, it is possible to deliver highly selective radiation doses to solid tumours using intratumour injection of alpha-particle-emitting RICs. Improved tumour retention caused by antigen binding indicates that reduced normal tissue exposure can be obtained with antigen-specific antibodies. The heterogeneous tumour dose distribution observed is, however, a major impediment to the use of alpha-particle emitters against solid tumours.

Topics: Animals; Astatine; Autoradiography; Humans; Immunoglobulins; Injections, Intralesional; Mice; Mice, Nude; Osteosarcoma; Radioimmunotherapy; Subrenal Capsule Assay

The potential usefulness of alpha-particle radioimmunotherapy in the treatment of osteosarcoma was studied in vitro by using the monoclonal antibody TP-3 and cells of three human osteosarcoma cell lines (OHS, SAOS and KPDX) differing in antigen expression. Cell survival curves were established after treatment with (a) 211At-TP-3 of different specific activities, (b) 211At-labeled bovine serum albumin (BSA), (c) free 211At and (d) external-beam X rays. The three osteosarcoma cell lines showed similar survival curves, whether treated with external-beam X rays, 211At-BSA or free 211At. The D0's were lower for free 211At than for 211At-BSA. The survival curves for 211At-TP-3 treatment, on the other hand, differed significantly among the cell lines, suggesting that sensitivity to 211At-TP-3 treatment was governed by cellular properties other than sensitivity to external-beam X rays. The cellular property most important for sensitivity to 211At-TP-3 treatment was the antigen expression. Cell inactivation after 211At-TP-3 treatment increased substantially with increasing specific activity of the 211At-TP-3. At high specific activities, the cytotoxic effect of 211At-TP-3 was significantly higher than that of 211At-BSA. In conclusion, 211At-TP-3 has the potential to give clinically favorable therapeutic ratios in the treatment of osteosarcoma.

Topics: Antibodies, Monoclonal; Astatine; Bone Neoplasms; Cell Survival; Humans; Osteosarcoma; Radioimmunotherapy; Radiotherapy Dosage; Serum Albumin, Bovine; Tumor Cells, Cultured; X-Rays

Microcolonies were obtained by culturing cells of two human osteosarcoma lines (OHS and KPDX) and one human melanoma line (WIX-c) for either 24 or 72 h. The microcolonies were treated with either alpha-particle radiation emitted by the 211At-labelled monoclonal antibody (MAb) TP-3 or external beam X-rays. Survival of microcolonies was assayed by colony formation. Therapeutic gain factor (TGF) values were calculated for two survival levels, 50% and 20% microcolony regeneration (i.e. at least one cell in 50% or 20% of the colonies survived the treatments). The TGF values were affected by the specific activity of the 211At-MAb conjugate, the antigen expression of the cells and the size and growth pattern of the microcolonies. Treatment with 211At-TP-3 gave TGF values that varied from 1.3 +/- 0.4 to 4.5 +/- 0.7 (mean +/- s.e.). The antigen-rich OHS cell line had on average 1.6 times higher TGF than the antigen-poor KPDX cell line. The TGF increased significantly with colony size for the densely packed colonies of the KPDX cell line but not for the OHS cell line, which had colonies with cells growing in a more scattered pattern. Control experiments with the two non-specific 211At forms, free 211At and 211At-labelled bovine serum albumin, gave TGF values from 0.6 +/- 0.1 to 1.0 +/- 0.3. This study suggests that in vivo evaluation of 211At-MAbs using relevant tumour models is desirable.

Topics: Antibodies, Monoclonal; Astatine; Bone Neoplasms; Cell Division; Cell Line; Humans; Immunoglobulin G; Melanoma; Models, Biological; Osteosarcoma; Radioimmunotherapy; Tumor Cells, Cultured; X-Rays