William F. Goeckeler

The use of chelated radionuclide (samarium-153-ethylenediaminetetramethylenephosphonate) to modulate phenotype of tumor cells and enhance T cell-mediated killing.

Purpose: Exposing human tumor cells to sublethal doses of external beam radiation up-regulates expression of tumor antigen and accessory molecules, rendering tumor cells more susceptible to killing by antigen-specific CTLs. This study explored the possibility that exposure to palliative doses of a radiopharmaceutical agent could alter the phenotype of tumor cells to render them more susceptible to T cell–mediated killing. Experimental Design: Here, 10 human tumor cell lines (4 prostate, 2 breast, and 4 lung) were exposed to increasing doses of the radiopharmaceutical samarium-153-ethylenediaminetetramethylenephosphonate (153Sm-EDTMP) used in cancer patients to treat pain due to bone metastasis. Fluorescence-activated cell sorting analysis and quantitative real-time PCR analysis for expression of five surface molecules and several tumor-associated antigens involved in prostate cancer were done. LNCaP human prostate cancer cells were exposed to 153Sm-EDTMP and incubated with tumor-associated antigen-specific CTL in a CTL killing assay to determine whether exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to T cell–mediated killing. Results: Tumor cells up-regulated the surface molecules Fas (100% of cell lines up-regulated Fas), carcinoembryonic antigen (90%), mucin-1 (60%), MHC class I (50%), and intercellular adhesion molecule-1 (40%) in response to 153Sm-EDTMP. Quantitative real-time PCR analysis revealed additional up-regulated tumor antigens. Exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to killing by CTLs specific for prostate-specific antigen, carcinoembryonic antigen, and mucin-1. Conclusions: Doses of 153Sm-EDTMP equivalent to palliative doses delivered to bone alter the phenotype of tumor cells, suggesting that 153Sm-EDTMP may work synergistically with immunotherapy to increase the susceptibility of tumor cells to CTL killing.

Organis amine phosphonic acid complexes for the treatment of calcific tumors

Particle-emitting radionuclides, e.g. Samarium-153, have been complexed with organic aminoalkylenephosphonic acids wherein the nitrogen and phosphorus are interconnected by an alkylene group or substituted alkylene group. These complexes have been found useful in compositions for the therapeutic treatment of calcific tumors in animals.

Biodistribution and preclinical radioimmunotherapy studies using radiolanthanide‐labeled immunoconjugates

Lutetium‐177 (177Lu), samarium‐153 (153Sm), and yt‐trium‐90 (90Y) are members of the family of elements known as lanthanides or rare earths. Monoclonal antibody CC49, a murine immunoglobulin (Ig) G1, which is reactive with the tumor‐associated antigen TAG‐72, previously has been shown to react with a wide range of human carcinomas. The authors review here the comparative biodistributions of CC49 IgG and F(ab′)2 fragments labeled with 177Lu, 153Sm, and 90Y using the bifunctional chelating agent PA‐DOTA. The authors also review the results of a biodistribution study comparing iodine‐125‐labeled and 177Lu‐labeled CC49 sFv, and the use of 177Lu‐CC49 IgG in an experimental therapy model. Chelation and conjugations gave similar yields, and the labeled proteins showed similar retention of immunoreactivity regardless of the isotope used for both IgG and F(ab′)2. Biodistribution data obtained in athymic mice bearing LS‐174T human colon carcinoma xenografts likewise showed no differences among the three radioisotopes for both IgG and F(ab′)2. Femur uptake of radioactivity was lower than previously reported for other radiolanthanide immunoconjugates. Different metabolic patterns were observed for radioiodinated versus radiometal‐la‐beled sFv, particularly in the kidney, where localization of the latter was increased dramatically. 177Lu‐CC49 was found to delay the growth of established LS‐174T human colon carcinomas in athymic mice at a single dose of 50 μCi. Elimination of established tumors was demonstrated over the observation period (77 days) using single administrations of 200 or 350 μCi. Dose fractionation experiments revealed that the mice tolerated 750 μCi (3 × 250 μCi, given weekly), whereas > 50% of the mice died after receiving a single administration of ∼ 500 μCi. In iso‐type‐matched control experiments, a large differential in the therapeutic effects was observed between 177Lu‐la‐beled control antibody and CC49. Cancer 1994; 73:993–8.

Radioactive compositions for the treatment of calcific tumors

Certain particle-emitting radionuclides, e.g. Samarium-153, have been complexed with certain alkylenepolyaminocarboxylic acid chelants. Compositions containing these complexes have been found useful in the treatment of calcific tumors in animals. The stability constant, log K, of the useful complexes is from about 14 to about 17 and the molar ratio of chelant to radionuclide in the compositions is such that the chelant is present in an amount sufficient to inhibit uptake of the radionuclide by soft tissue.

Analysis of urine samples from metastatic bone cancer patients administered 153Sm-EDTMP

153Sm-EDTMP is currently undergoing clinical evaluation as a radiotherapeutic agent for the relief of pain associated with cancer metastatic to bone. These clinical studies have demonstrated biodistributions similar to those seen earlier in animals, namely, rapid clearance from blood, selective uptake in bone and in particular metastatic bone lesions. The radioactivity not deposited in bone is cleared through the kidneys into the urine. In this study, urine samples collected from 9 patients injected with 153Sm-EDTMP underwent complexation analysis via Pharmacia SP-Sephadex C25 cation exchange chromatography. The results showed 96.9 +/- 1.7% of the radioactivity in the urine to be present as a complex of 153Sm. An HPLC method was developed and it was demonstrated that different complexes of 153Sm could be separated. A non-radioactive analytical standard of the Sm-EDTMP chelate was synthesized, characterized and shown to have the same HPLC retention profile as the 153Sm-EDTMP drug product. HPLC analysis was performed on six urine samples and in each case a single radioactivity peak with an elution profile the same as that of a 153Sm-EDTMP standard was observed. These results indicate that the 153Sm-EDTMP chelate is excreted intact in the urine of patients.