Progenics Pharmaceuticals, Inc. (Tarrytown, NY), has granted an exclusive license to Bayer for the development and commercialization of therapeutic antibodies combining the Progenics’s prostate specific membrane antigen (PSMA) antibody technology with Bayer’s targeted thorium conjugate technology.

Prostate cancer is the second most common form of cancer affecting men in the United States: an estimated one in seven men will be diagnosed with prostate cancer in his lifetime. The American Cancer Society estimates that each year approximately 220,800 new cases of prostate cancer will be diagnosed and about 27,540 men will die of the disease. Approximately 2.9 million men in the U.S. currently count themselves among prostate cancer survivors.

“While there have been recent advances in the treatment of prostate cancer, there remains a great need for therapies that can more specifically target primary and metastatic prostate cancer,” said Mark R. Baker, Chief Executive Officer of Progenics.

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“This license agreement with Bayer further validates the value of our PSMA antibody technology in the development of targeted cancer treatments. We are pleased that Bayer recognizes the potential of our technology,” Baker continued.

Metastatic prostate cancer
PSMA is a protein that has been found to be amplified on the surface of >95% of prostate cancer cells and is a validated target for the detection of primary and metastatic prostate cancer.

Antibody-thorium conjugates are comprised of a radioactive alpha emitter, thorium-227, linked to an antibody, in this case PSMA. Thorium emits very energy-rich radiation over a (very) short distance. The thorium conjugates bind to the surface of tumor cells and emit alpha particles that destroy tumor cells by inducing DNA double-strand breaks, with no need for uptake into the cells for efficacy.

To be successful, a precise calculation of the radiation dose and targeted delivery to the desired cancer site is required.  Conjugating radioactive compound to an antibody guarantees the targets delivery.  Bayer’s targeted thorium conjugate technology was originally developed by Norwegian based Aleta ASA, a company acquired by Bayer in 2013.

PSMA ADC
Progenies is developing a range of therapeutic agents designed to precisely target cancer, including a novel PSMA ADC.  The company’s PSMA ADC comprises a fully human monoclonal antibody selectively targeting PSMA linked to a chemotherapeutic drug. Using technology licensed from Seattle Genetics, the PSMA antibody is linked to monomethyl auristatin E, a compound that inhibits cell proliferation by disrupting the cellular “backbone” (i.e. microtubules) required for replication.

The resultant antibody-drug conjugate attaches to the PSMA protein on the surface of prostate cancer cells and is designed to internalize into the cancer cell, release active anti-cancer drug, and destroy the malignant cell. Unlike traditional chemotherapy, PSMA ADC is designed to deliver the drug selectively to prostate cancer cells by targeting PSMA.

Earlier Robert J. Israel, M.D., Executive Vice President, Medical Affairs at Progenies noted “the PSMA ADC is the most advanced antibody drug conjugate in clinical development to treat prostate cancer, [and] based on data seen [..] in chemotherapy experienced patients, we have decided to explore whether this compound can also benefit men in the less clinically advanced chemotherapy naïve setting.”

Imaging agent
Progenics is also developing a PSMA-targeted imaging agents for prostate cancer (1404 and PyL) intended to enable clinicians and patients to accurately visualize and manage their disease.

This PSMA-targeting image agent 1404 is a molecular imaging radiopharmaceutical designed to targets the extracellular domain of prostate specific membrane antigen. 1404 is labeled with Technetium-99m, a gamma-emitting isotope that is widely available, is easy to prepare, and is attractive for nuclear medicine imaging applications. The image created provides the opportunity to visualize cancer, potentially allowing for improved detection and staging, more precise biopsies, and a targeted treatment plan including active surveillance as a disease management tool.

In January 2016 the company begun enrollment in its pivotal Phase III clinical trial evaluating 1404, a small molecule being developed as an imaging agent for prostate cancer. 1404 targets prostate  PSMA, which is abundantly expressed on prostate cancer cells.

This Phase III clinical trial is expected to enroll approximately 450 patients with newly diagnosed low-grade prostate cancer who are candidates for active surveillance, but nonetheless are planning to undergo radical prostatectomy. This multi-center, open-label trial will evaluate the sensitivity and specificity of 1404 in correctly identifying whether or not patients have clinically significant prostate cancer (generally, Gleason score >3+4). In this trial, patients will be imaged prior to their scheduled radical prostatectomy. The truth standard in establishing the sensitivity and specificity of 1404 will be the histopathologist’s grading of the prostate tissue removed in the prostatectomy, which will be compared to the 1404 image assessments. An interim analysis of the study will be performed after approximately one-third of the subjects have been enrolled to assess futility and evaluate the need for a sample size re-estimation.

“An imaging agent like 1404, which may discriminate clinically significant prostate cancer from indolent disease, would provide a useful tool for disease management and treatment, as well as further supporting the use of active surveillance,” explained William J. Ellis M.D., Professor, Department of Urology, University of Washington School of Medicine and Lead Investigator for the Phase III Study.

“The goal of active surveillance is to monitor low-grade disease and avoid the risks and complications associated with unnecessary surgical or therapeutic treatments; however, biopsies and other measures currently used to monitor disease progression have their own limitations and risks, curtailing the broader use of active surveillance,” Ellis added.

“Commencing this Phase III study represents a significant step forward in the clinical development of 1404 and our efforts to bring forward a portfolio of PSMA-targeted imaging agents to help detect and monitor prostate cancer,”Progenics’ Mark Baker further noted.

Agreement
Per the terms of the license agreement, Progenics will receive an upfront fee and could receive additional potential clinical and regulatory development milestones. If approved, Progenics is entitled to single digit royalties and sales milestone payments.


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ADC Review, Journal of Antibody-drug Conjugates (ISSN 2327-0152) launched in 2013, is designed to serve the needs of a diverse community of individuals including academia, life sciences, pharma, (basic, translational and clinical) research, clinicians/physicians, along with regulatory affairs, government authorities and representatives from payers, and policy makers. The Journal’s content includes peer reviewed research, commentaries, news features, discussions, editorials and blogs on topics relevant to a broad international readership. The Journal also offers a knowledge center (called ADC University) offering the latest and most relevant information about Antibody-drug Conjugates (ADCs), BiSpecific Antibodies, Site Specific Antibody Drug Conjugates, Small Molecule Drug Conjugates (SMDC), and Engineered Antibody Fragments. The purpose of the Journal is to present this information in an understandable and a useful format for all stakeholders.