~(177)Lu-DOTA-J591 MONOCLONAL ANTIBODY: CHEMISTRY, TOXICITY, DOSIMETRY AND CLINICAL EFFICACY: RIT OF PROSTATE CANCER USING ~(177)LU-J591 ANTI-PSMA ANTIBODY

摘要

Prostate specific membrane antigen (PSMA) is a transmembrane antigen virtually restricted to prostate tissue and the expression of which is increased in prostate carcinoma. Indium-111 capromab pendetide (ProstaScint~R) is an antibody specific to the intracellular epitope of PSMA. For the past several years, the authors have been engaged in the development and evaluation of a radiolabelled humanized monoclonal antibody, J591, specific to an extracellular epitope of PSMA. After demonstrating that J591 is internalized, the authors developed ~(90)Y and ~(177)Lu labelled DOTA-J591 for radio-immunotherapy of prostate cancer. These radiometals remain localized in tumour foci (as well as other tissues including non-specific hepatic uptake) compared to ~(131)I labelled proteins. In contrast to ~(90)Y, ~(177)Lu is a radiometal with a low energy β~- emission as well as a y photon emission that makes it convenient to demonstrate localization and quantify biodistribution and turnover externally. Metastatic prostate carcinoma, in particular, is an ideal target for radioimmunotherapy since chemotherapeutic or other medical therapies are not ideal or appropriate. All human studies were approved by the institutional IRB and were performed as a phase I dose escalation study under an IND. Initially, different doses of J591 were used to assess the influence of total protein content on biodistribution. From these studies, it was determined that 10 mg/m~2 total protein per patient was sufficient to reduce non-specific organ uptake, potentially optimizing tumour access to labelled antibody. With ~(177)Lu-J591, dose limiting haematological toxicity was observed at 2590 MBq/m~2. In 35 patients, the appearance and severity of myelotoxicity correlated with the calculated bone marrow radiation absorbed dose. Response in terms of significant decreases in PSA, bone flare phenomena followed by improvement in bone scan findings have been observed but only in a single dose trial; relapse has occurred suggesting that further evaluation with multidose administration at ≤MTD or therapy in combination with radiosensitizing chemotherapy may be necessary.