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

A novel α-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 213 Bi radiometal ion. Bismuth-213 is a short-lived (t 1/2 = 46 min) radionuclide that emits high energy α-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. [ 213 Bi]J591 was specifically cytotoxic to LNCaP. The LD 50 value of[ 213 Bi]J591 was 220 nCi/ml at a specific activity of 6.4 Ci/g. The potency and specificity of [ 213 Bi]J591 directed against LNCaP spheroids, an in vitro model for micrometastatic cancer, also was investigated.[ 213 Bi]J591 effectively stopped growth of LNCaP spheroids relative to an equivalent dose of the irrelevant control[ 213 Bi]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. [ 213 Bi]J591 was able to significantly improve ( P < 0.0031) median tumor-free survival (54 days) in these experiments relative to treatment with irrelevant control[ 213 Bi]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 [ 213 Bi]HuM195), and 28 ng/ml +/− 22 ng/ml ( n = 6, animals treated with[ 213 Bi]J591). The reduction of PSA levels in mice treated with [ 213 Bi]J591 relative to mice treated with[ 213 Bi]HuM195 and untreated control animals was significant with P < 0.007 and P < 0.0136, respectively. In conclusion, a novel [ 213 Bi]-radiolabeled J591 has been constructed that selectively delivers α-particles to prostate cancer cells for potent and specific killing in vitro and in vivo .