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An -Particle Emitting Antibody ([²¹³Bi]J591) for Radioimmunotherapy of Prostate Cancer¹

Departments of Pharmacology and Molecular Therapeutics [M. R. M., E. B., D. M., L. L., M. J. C., V. P., M. L., D. A. S.], Radiology [R. D. F.], Pathology [C. C-C.], and Medical Physics [G. S., Å. M. B., W-H. Y.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Department of Urology, New York Presbyterian Hospital-Weill Medical College of Cornell University and Ludwig Institute for Cancer Research, New York, New York 10021 [N. H. B.]; Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [M. W. B.]; and Pharmactinium, Inc., Chevy Chase, Maryland 20815 [M. W. G.]

A novel -particle emitting monoclonal antibody construct targeting the external domain of prostate-specific membrane antigen (PSMA) was prepared and evaluated in vitro and in vivo. The chelating agent, N-[2-amino-3-(p-isothiocyanatophen-yl)propyl]-trans-cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid, was appended to J591 monoclonal antibody to stably bind the ²¹³Bi radiometal ion. Bismuth-213 is a short-lived (t_1/2 = 46 min) radionuclide that emits high energy -particles with an effective range of 0.07–0.10 mm that are ideally suited to treating single-celled neoplasms and micrometastatic carcinomas. The LNCaP prostate cancer cell line had an estimated 180,000 molecules of PSMA per cell; J591 bound to PSMA with a 3-nM affinity. After binding, the radiolabeled construct-antigen complex was rapidly internalized into the cell, carrying the radiometal inside. [²¹³Bi]J591 was specifically cytotoxic to LNCaP. The LD₅₀ value of [²¹³Bi]J591 was 220 nCi/ml at a specific activity of 6.4 Ci/g. The potency and specificity of [²¹³Bi]J591 directed against LNCaP spheroids, an in vitro model for micrometastatic cancer, also was investigated. [²¹³Bi]J591 effectively stopped growth of LNCaP spheroids relative to an equivalent dose of the irrelevant control [²¹³Bi]HuM195 or unlabeled J591. Cytotoxicity experiments in vivo were carried out in an athymic nude mouse model with an i.m. xenograft of LNCaP cells. [²¹³Bi]J591 was able to significantly improve (P < 0.0031) median tumor-free survival (54 days) in these experiments relative to treatment with irrelevant control [²¹³Bi]HuM195 (33 days), or no treatment (31 days). Prostate-specific antigen (PSA) was also specifically reduced in treated animals. At day 51, mean PSA values were 104 ng/ml +/- 54 ng/ml (n = 4, untreated animals), 66 ng/ml +/- 16 ng/ml (n = 6, animals treated with [²¹³Bi]HuM195), and 28 ng/ml +/- 22 ng/ml (n = 6, animals treated with [²¹³Bi]J591). The reduction of PSA levels in mice treated with [²¹³Bi]J591 relative to mice treated with [²¹³Bi]HuM195 and untreated control animals was significant with P < 0.007 and P < 0.0136, respectively. In conclusion, a novel [²¹³Bi]-radiolabeled J591 has been constructed that selectively delivers -particles to prostate cancer cells for potent and specific killing in vitro and in vivo.

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