Elsevier

Seminars in Oncology

Volume 30, Issue 5, October 2003, Pages 667-676
Seminars in Oncology

Targeted systemic therapy of prostate cancer with a monoclonal antibody to prostate-specific membrane antigen

https://doi.org/10.1016/S0093-7754(03)00358-0Get rights and content

Abstract

For the last 60 years, hormonal therapy has been the cornerstone of treatment of metastatic prostate cancer. Unfortunately, hormonal therapy is purely palliative and improved systemic therapies are necessary. Monoclonal antibodies (mAbs) have proven valuable in the treatment of several diseases including cancer. mAbs act by focusing an immune response on or by targeting delivery of highly cytotoxic agents to the cancer cells without targeting normal cells. Prostate-specific membrane antigen (PSMA) has been identified as an ideal antigenic target in prostate cancer. PSMA is the most well-established, highly restricted prostate cancer cell surface antigen. It is expressed at high density on the cell membrane of all prostate cancers, and after antibody binding, the PSMA-antibody complex is rapidly internalized along with any payload carried by the antibody. J591 is the first IgG mAb developed to target the extracellular domain of PSMA, and it has been deimmunized (humanized) to allow repeated dosing in patients. Three phase I studies are in progress, two using the β-emitting radiometals yttrium 90 and lutetium 177, and a third using a cytotoxin (DM1) linked to J591. Imaging of patients after they have received radiolabeled J591 demonstrates excellent tumor targeting.

Section snippets

Prostate-specific membrane antigen

Prostate-specific membrane antigen (PSMA) is the single most well-established, highly restricted prostate epithelial cell membrane antigen known.2, 3, 4, 5, 6, 7The gene has been cloned, sequenced,3 and mapped to chromosome 11p.8 Although first thought to be entirely prostate-specific,2, 3, 4 subsequent studies demonstrated that PSMA is also expressed by cells of the small intestine, proximal renal tubules, and salivary glands.6 However, the level of expression in these nonprostate tissues is

Monoclonal antibodies to PSMAext

Following our hypothesis, we produced the first series of IgG mAbs to PSMAext (J591, J415, J533, and E99).18 Enzyme-linked immunosorbent assays (ELISAs) confirmed that these mAbs to PSMAext bound to the same molecule as 7E11 but did not compete with 7E11 for binding.18 Immunoprecipitation and Western blot assays confirmed unmistakably that these mAbs bound to the 100-kd PSMA.18 In contrast to 7E11/CYT-356, these mAbs recognize two distinct epitopes located on the exterior of the cell.18, 19

Conclusion

PSMA represents an ideal cell surface protein for targeted therapy of prostate cancer and vasculotoxic therapy of nonprostate solid cancers. Clinical trials using mAb J591, which recognizes the extracellular domain of PSMA, indicate that this antibody can effectively target disseminated prostate and non-prostate cancers in patients. Furthermore, J591 can be used to deliver radioisotopes or other cytotoxins to these cancer sites. Major, objective responses have been seen in the phase I prostate

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    Supported in part by NIH General Clinical Research Centers Program (NCRR Grant No. M01RR00047); US Department of Army (DAMD17-98-1-8594), Cancer Research Institute, Cap Cure, the David H. Koch Foundation, the Peter Sacerdote Foundation, BZL Biologics, Inc, and Millennium Pharmaceuticals, Inc. N.H.B. developed the J591 antibody used in this study. J591 and related anti-PSMAext antibody patents were assigned to the Cornell Research Foundation and subsequently licensed to BZL Biologics, Inc. N.H.B. is a paid consultant to BZL Biologics, Inc.

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