Antibody therapeutics for treating prostate cancer: where are we now and what comes next?

ABSTRACT

Introduction: Progress in the understanding of molecular events of carcinogenesis and cancer evolution as well as the identification of tumor antigens has led to the development of different targeted therapeutic approaches, including the use of monoclonal antibodies (mAbs). Prostate cancer (PC) is highly amenable to mAb targeting given the existence of prostate-specific targets and the natural history and localization of metastatic disease.

Areas covered: Several aspects of the PC phenotype, including growth factors, angiogenesis mediators, bone microenvironment signals, and immune evasion pathways, have become areas of ongoing investigation in terms of mAb targeting. These are reviewed. The greatest success so far has been the development of mAbs against prostate-specific tumor antigen (PSMA), which opened an opportunity to improve diagnostic accuracy and simultaneously target metastatic disease.

Expert opinion: As mAb use in PC continues to evolve, more accurate imaging of the extent of disease and more effective mAb therapies (naked or conjugated with drugs, toxins or radioactive molecules) are emerging. In addition, the combination of mAbs with other treatment modalities is expected to further improve responses and overall survival. Identification of validated biomarkers is necessary for better recognition of patient subgroups who will derive the greatest benefit from mAb therapy.

KEYWORDS:

• Immunotherapy
• monoclonal antibody
• prostate cancer
• prostate-specific membrane antigen
• targeted therapy

Article highlights

• Monoclonal antibody (mAb) therapies have revolutionized the way we approach cancer treatment, in terms of enabling targeted cytotoxicity as well as specific imaging, resulting in earlier recognition of relapses and less off-target systemic adverse effects.

• Prostate cancer (PC) is a targetable malignancy given the specificity of some tumor antigens for prostate tissue and the avidity of metastases for blood-enriched areas, such as bone and lymphatic tissues.

• Prostate specific membrane antigen (PSMA) represents an excellent target, exploitation of which has resulted in the FDA approval of the first radiolabeled mAb (¹¹¹In-capromab pendetide) and encouraging phase I and II data from radiolabeled mAb and mAb-drug conjugates.

• Targeting of the bone microenvironment with the FDA-approved mAb denosumab has offered another viable therapeutic option, both in the non-metastatic setting for the prevention of osteoporotic fractures and in the metastatic setting for risk-reduction of skeletal-related events.

• Immunotherapy in the form of immune checkpoint inhibition was initially promising, but subsequently disappointing in targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) with ipilimumab, but there is renewed interest in checkpoint inhibition with programmed cell death protein 1 (PD-1) mAbs.

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Declaration of interest

ST Tagawa has received research support via his institution from Eli Lilly and Company, Sanofi, Janssen Pharmaceuticals, Astellas, Progenics, Millennium, Amgen Inc, Bristol-Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer Healthcare and Genentech. They have also received consulting honoraria from Astellas, Dendreon, Janssen Pharmaceuticals, Bayer Healthcare, Genentech and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript was funded by Weill Cornell Medical College, New York, USA.