An alpha-particle emitting antibody ([Bi-213]J591) for radioimmunotherapy of prostate cancer

A novel Lu-particle emitting monoclonal antibody construct targeting the ex ternal domain of prostate-specific membrane antigen (PSMA) was prepared and evaluated in vitro and bl vivo, The chelating agent, N-[2-amino-3-(p-isoth iocyanatophen-yl)propyl]-trans-cyclohexane-1,2-diamine-N,N',N',N",N"-pentaa cetic acid, was appended to J591 monoclonal antibody to stably bind the Bi- 213 radiometal ion. Bismuth-213 is a shortlived (t(1/2) = 46 min) radionucl ide that emits high energy or-particles with an effective range of 0.07-0.1 0 mm that are ideally suited to treating single-celled neoplasms and microm etastatic 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 radio-labeled construct-antigen complex was rapidly in ternalized into the cell, carrying the radiometal inside. [213Bi]J591 was s pecifically cytotoxic to LNCaP. The LD50 value of [Bi-213]J591 was 220 nCi/ ml at a specific activity of 6.4 Ci/g. The potency and specificity of [Bi-2 13]J591 directed against LNCaP spheroids, an in vitro model for micrometast atic cancer, also was investigated. [Bi-213]J591 effectively stopped growth of LNCaP spheroids relative to an equivalent dose of the irrelevant contro l [Bi-213]HuM195 or unlabeled J591, Cytotoxicity experiments in vivo were c arried out in an athymic nude mouse model with an i.m. xenograft of LNCaP c ells. [Bi-213]J591 was able to significantly improve (P < 0.0031) median tu mor-free survival (54 days) in these experiments relative to treatment with irrelevant control [Bi-213]HuM195 (33 days), or no treatment (31 days). Pr ostate-specific antigen (PSA) was also specifically reduced in treated anim als. At day 51, mean PSA values were 104 ng/ml +/- 54 ng/ml (n = 4, untreat ed animals), 66 ng/ml +/- 16 ng/ml (n = 6, animals treated with [Bi-213]HuM 195), and 28 ng/ml +/- 22 ng/ml (n = 6, animals treated with [Bi-213]J591). The reduction of PSA levels in mice treated with [Bi-213]J591 relative to mice treated with [Bi-213]HuM195 and untreated control animals was signific ant with P < 0.007 and P < 0.0136, respectively. In conclusion, a novel [Bi -213]-radiolabeled J591 has been constructed that selectively delivers <alp ha>-particles to prostate cancer cells for potent and specific killing irt vitro and in vivo.