Therapeutic Target Candidates

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Human cancers represent a group of highly heterogeneous lesions consisting of morphologically distinct subtypes, with different molecular/biochemical signatures, both between and within tumors.
Recent work indicates that a small population of cells endowed with unique self-renewal properties and tumorigenic potential is present in all tumors. These so-called tumor stem cells with their specific features are thought to be at the basis of cancer progression, metastasis and resistance to treatment.

Stem cells possess three major and distinct clinical properties: (1) they are undifferentiated; (2) they have the potential to divide indefinitely and (3) can give rise to different somatic cell types.
However, despite intensive research and tumor model xenografts, progenitor stem cells still hold their secrets and specific molecular signatures. A number of supposedly discovered progenitor stem cell genes were shown to be expressed in many normal tissues, which makes it difficult to use them as therapeutic candidate targets.

Cancer heterogeneity can arise from the differentiation of stem-like cells along with the clonal selection that occurs during cancer progression, and such heterogeneity represents a major challenge for the design of effective therapies. At Phenotype Pharmaceuticals we designed a set of technologies that not only allow us to discover potentially relevant therapeutic target candidates, but more importantly to identify those that transcend the extensive heterogeneity frequently observed in cancers. These candidates are called CDCT®

Phenotype hypothesis

Phenotype hypothesizes that since cancer progenitor stem cells are known to be present in all tumors, these cells should express target specific molecules to all tumors. Such targets would be likely present throughout all stages of the disease independently of genders and ethnic differences and transcendent to the extensive tumor heterogeneity. We refer to these targets as “common denominator tumor target -CDCT™-”, and as such they would be an ideal therapeutic target whether for small molecule, vaccine or antibody therapeutics.

If “CDCT™” were to exist, they would be ideal target candidates for all tumors and to the majority of the patient population, regardless of disease stage. Therapeutic intervention based on common denominator tumor targets would benefit most patients, in contrast to cancer targets currently in use such as Her-2, which is only present in about 30% of late stage breast cancer patients.

“CDCT™” would be ideal target candidates for all tumors and to the majority of the patient population, regardless of disease stage

Specific tumor progenitor stem cells

Phenotype has devoted many years of research focusing on developing proprietary technologies and tools to validate the proof of concept of tumor stem cell “CDCT™” that are expressed by all tumor progenitor stem cells.

Phenotype discovery and validation process of clinical therapeutic targets relies on three pillars:

    Phenotype employs subtractive molecular tools and other proprietary technologies to generate specific monoclonal antibody libraries, against molecules expressed by tumor progenitor stem cells of different tissue origins.

      Phenotype uses a proprietary screening platform to analyze appropriate clinical samples with the specific monoclonal antibody libraries in order to identify optimal “CDCT™” of tumor progenitor cell targets for therapeutic intervention.

       Identified targets are further thoroughly characterized with monoclonal antibodies to validate the proof of concept of tumor specificity on a very large collection of patient clinical specimens.
Attributes of our therapeutic antibodies.

At Phenotype Pharmaceuticals we are working diligently to implement several key attributes in our therapeutic antibodies:

        1. High specificity. A good therapeutic antibody must specifically bind its target molecule on the tumor cell surface to neutralize important physiological functions in the target cell.

           2. High affinity. A good therapeutic antibody must also possess a strong affinity for its target, to ensure the most effective reactivity. High affinity may also result in reducing the cost of treatment by reducing the dose required to neutralize the antigenic target.

               3. Low cross-reactivity. The toxicity potential of an antibody is tied in part to the specificity with which the antibody binds to its target antigen. A good therapeutic monoclonal antibody with high specificity and high affinity is necessarily an antibody that exhibits low cross reactivity with other human tissue antigens.

        4. High prevalence. A good therapeutic target for a given disease is one that is expressed in the majority of the patient population. A major challenge in the pharmaceutical and biotechnology industry has always been to identify disease targets that are not only specific for the disease, but that are also present in most patients with the disease. In contrast, Her-2 as well as other targets against which antibody therapeutics have been developed, are only expressed in a fraction of patients, thus ultimately limiting the use of the corresponding drug to a subset of the relevant patient population.

          5. Tolerance. A good therapeutic monoclonal antibody is a humanized one designed to provide maximum tolerance to the patients, ensuring high penetrance and longer half-life, as well as optimal efficiency against its target, and maximum tolerance by patient’s immune system.

Related Publications

Alain Beck, Thierry Wurch, Christian Bailly and Nathalie Corvaia. Strategies and challenges for the next generation of therapeutic antibodies. Nature Reviews, Immunology. Volume 10, p. 345-352. May, 2010.

Douglas Hanahan and Robert A. Weinberg. Hallmarks of Cancer: The Next Generation
Cell 144, March 4, p646-674. 2011

Janice M Reichert. Antibodies to watch in 2014. Antibodies to watch in 2014, mAbs, 6:1, 5-14,
http://dx.doi.org/10.4161/mabs.27333

Andrew C. Chan and Paul J. Carter. Therapeutic antibodies for autoimmunity and inflammation. Nature Reviews, Immunology. Volume 10, p. 345-352. May, 2010.

Ferdinando Mannello. Understanding breast cancer stem cell heterogeneity: time to move on to a new research paradigm BMC Medicine, 11:169- 2013

Thomas Klonisch, Emilia Wiechec, Sabine Hombach-Klonisch, Sudharsana R. Ande, Sebastian Wesselborg, Klaus Schulze-Osthoff and Marek Los. Cancer stem cell markers in common cancers – therapeutic implications. Trends in Molecular Medicine Vol.xxx No.x. Cell.

Tannishtha Reya, Sean J. Morrison, Michael F. Clarke, Irving L. Weissman. Stem cells, cancer, and cancer stem cells. Nature, Vol. 414 | 1 November, 105-111. 2001

Arokia Priyanka Vaz, Moorthy P. Ponnusamy, Parthasarathy Seshacharyulu , and Surinder K. Batra. A concise review on the current understanding of pancreatic cancer stem cells. Journal of Cancer Stem Cell Research, 2:e1004, 2014.