Monoclonal antibody therapy for prostate cancer: finally a reality?

The development of monoclonal antibody therapy targeted at tumor antigens for the treatment of cancer has had some stunning successes: trastuzumab for HER2positive breast cancer, rituximab for CD20-positive nonHodgkin’s lymphomas, cetuximab for EGFR-positive colorectal carcinoma, and gemtuzumab for CD33positive myeloid malignancies. However, until now, prostate cancer has been notably absent from these successes. This is partly due to a lack of identified prostateor prostate cancer–restricted antigens or cell surface molecules that can serve as targets. Two well-established antigens, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), have been well explored in a variety of immunotherapeutic strategies. Most investigators acknowledge, however, that targeting these particular antigens is problematic because of the large “sink” represented by large secreted pools of antigen. The work reported by Milowsky et al in this issue of the Journal of Clinical Oncology utilizing the monoclonal antibody J591 against prostate-specific membrane antigen (PSMA) is significant in this context. In many ways, PSMA represents an ideal target on prostate cancer cells. PSMA expression appears to correlate directly with aggressive biologic behavior, and has more robust expression in highgrade tumors compared with low-grade cancers, metastatic disease compared with localized disease, and hormone refractory compared with hormone sensitive disease. PSMA is not a secreted protein, but a cell-surface glycoprotein, making it a more attractive therapeutic target than PSA or PAP. Indeed, a radiolabeled murine antibody that binds to an intracellular epitope of PSMA is US Food and Drug Administration-approved as an imaging agent for soft tissue metastases in prostate cancer (Indium-111 capromab pendetide). While the ultimate clinical utility of this imaging agent is debatable, it nevertheless reflects the feasibilty of targeting PSMA. Just as PSMA appears to be an important target, J591 has several characteristics that set it apart as a promising agent. First, and perhaps most importantly, this antibody binds extracellular PSMA epitope(s), which allows enhanced targeting of prostate cancer cells, and potential for its internalization. Secondly, this murine antibody has been de-immunized by engineering it into a human immunoglobulin G1. This feature presumably avoids the issue of developing neutralizing human antimouse antibodies— and, as it turns out— human antihuman antibodies as well. Thus, J591 has the potential to both serve as a targeting agent, delivering toxic payloads, be they radioisotopes, toxins or chemotherapy, as well as to have direct cytotoxic effects by inducing antibody-dependent cellular cytotoxicity using naked antibody alone. Given an appropriate target, and a seemingly appropriate antibody, what then is the pathway to developing a clinically useful reagent? Previously, Bander et al undertook a phase I trial of J591 to define the dose of antibody to provide optimal tumor targeting. Armed with that information, this group now reports the results of a phase I trial with a therapeutic agent. J591 labeled with yttrium-90 (Y) is a pure -emitter which has many attractive characteristics as a radiopharmaceutical. The authors also indicate that there is an ongoing trial evaluating J591 linked to a chemotherapeutic agent. While not specifically addressed, it would appear from the data presented that the promise of antibody-dependent cellular cytotoxicity made possible by the use of a naked antibody has not been borne out, or at least not robustly enough to warrant further testing. That is unfortunate, since the commercial development of radiopharmaceuticals has not been an easy task. This well-conducted study elucidates some of these challenges. The phase I nature of this trial resulted in the study of a heterogeneous group of patients. The failure to use PSA JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 13 JULY 1 2004