Antibody-drug conjugates offer hope for the treatment of hormone resistant prostate cancer

DailyUpdates 17^th August, 2004: Researchers from Protein Design Laboratories report that an antibody-drug conjugate that links the chemotherapeutic agent Auristatin to a prostate cancer specific antibody, anti-TMEFF2 mAb, via a cathepsin B-sensitive linker prevents tumor growth in a murine model of prostate cancer.

Prostate cancer is one of the most common forms of solid tumors with 230,000 new cases expected to be identified this year in the alone.  Prognosis is often good with tumors being responsive to hormonal therapies.

While cytotoxic chemotherapy has been utilized for many years in a variety of different malignancies, it represents a poor second line treatment once hormone resistance develops in prostate cancer patients since such tumors are remarkably unresponsive to many chemotherapeutic agents. The development of hormone resistance therefore results in a dramatic drop in prostate cancer survival rate and a narrowing of therapeutic options for the clinician. This year it is expected that close to 30,000 Americans will die of prostate cancer. 

In 1999, the market for agents to treat prostate cancer totaled $US41.3 billion. The estimated annual market potential for treatments of hormone resistant prostate cancer is in excess of $400 million driving the development of new therapeutics.  As with other cancers the development of biologics including therapeutic antibodies represents an important future area of the prostate cancer market.

In 2003, the market for monoclonal antibodies in the treatment of cancer was just short of $2.8 billion and growing at a phenomenal rate. The market is fueled by leading products such as Rituxan and Herceptin.  In 1997, Rituxan became the first monoclonal antibody therapy to be approved in the for the treatment of cancer.  This agent targets CD20 on B-cells and is indicated for B-cell non-Hodgkin's lymphoma (NHL).  Herceptin, approved by the FDA in 1998, targets HER2 and is therefore indicated for the treatment of metastatic breast cancer.  Other products continue to demand more attention each year (for an analysis of therapeutic antibodies click here).

Particularly exciting is antibody-drug conjugate (ADC) technology which employs monoclonal antibodies (mAbs) to deliver conjugated chemotherapeutic agents to the tumor environment.  In the conjugated form the chemotherapeutic exhibits low cytotoxicity, thereby sparing non-target cells many of the toxic effects of traditional chemotherapy. However as the ADC approaches tumors, intracellular or secreted factors cleave and hence release the chemotherapeutic agent from the conjugated molecule thereby facilitating the targeted killing of cancer cells.

Seattle Genetics is one company actively involved in the development of ADC technology and they currently have two candidates based on the chemotherapeutic agent Auristatin in development.  SGN-35 is an ADC composed of a genetically engineered antibody targeted to the CD30 antigen that is conjugated to a derivative of Auristatin.  This conjugate is in development for the treatment of hematologic malignancies.  SGN-75 is a second ADC composed of an anti-CD70 mAb linked to an Auristatin derivative.  This conjugate is in development for the treatment of patients with renal cancer or hematologic malignancies. 

Seattle Genetics and Protein Design Laboratories are currently collaborating to further develop the ADC technology and the efficacy of a further conjugate has recently been reported in the journal Molecular Cancer Therapeutics.  In the August edition of this journal Daniel Afar and colleagues from Protein Design Laboratories report on the anti-cancer activity of Auristatin linked to a prostate cancer specific antibody.

TMEFF2, is a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor-like domain.  The protein has limited normal tissue distribution and is highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific mAb to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naive and hormone-resistant disease.

Afar et al linked an anti-TMEFF2 mAbs to Auristatin E via a cathepsin B-sensitive valine-citrulline linker. Cathepsin B is highly expressed by many metastasizing tumors and together the targeting of Auristatin E by anti-TMEFF2 mAbs and its selective release is compatible with high levels of tumor specificity. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2.

Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.

Source: Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer. Mol Cancer Ther. 2004 Aug;3(8):921-32

This article is highlighted in the August 17^th edition of DailyUpdates-Oncology, LeadDiscovery’s unique bulletin of breaking journal articles and press releases for the drug discovery community. 

To access the article and to view today’s edition of DailyUpdates-Oncology click here