Cancer stem cells (CSCs) are a subset of cells found in tumors that have stem-cell like characteristics, including the ability to differentiate into all cell types of a particular cancer. CSCs have been shown to be resistant to current standard of care therapies, and likely contribute to relapse of the disease after the initial therapy.
Tumor target identification
One of the major limitations of chemotherapy is the inability of anticancer drugs to discriminate between normal and cancer cells. Almost all members of the major categories of antineoplastic agents have considerable toxicity for normal cells. Antibody therapies that specifically target cancer cells can avoid this problem.
Cellerant's expertise enables us to phenotypically characterize and enrich for leukemic CSCs to identify novel targets for therapeutic monoclonal antibody development. Cellerant's focus has been on the isolation of CSCs from various hematological cancers and its target discovery effort involves global gene and proteomic profiling of the CSC using state-of-the-art sequencing and profiling technologies (Figure below). The primary objective of this effort is to identify target antigens that are selectively expressed in CSCs as well as in bulk tumor, but have minimal expression in normal tissues.
Antibody-based therapeutics can target a specific cancer cell population and can also be conjugated with a cytotoxic drug for greater efficacy (Figure below). Cellerant is employing an antibody drug conjugate (ADC) technology to take advantage of the specificity of antibodies to deliver a potent cytotoxic drug to the CSC. Therapeutics employing ADC technology have been successful in extending the lives of patients with Hodgkin's Lymphoma and Her2 positive breast cancers, and Cellerant is developing this technology to help extend the lives of patients suffering from acute myeloid leukemia (AML), high risk myelodysplastic syndrome (MDS), multiple myeloma (MM), and other cancers. Many factors such as target antigen selection, antibody properties, internalization, efficient delivery of linker-payload to the tumor site, linker stability, and choice of payload and conjugation technology influence the therapeutic window of ADCs. A major unmet challenge in the ADC technology field is to increase the therapeutic window of ADCs. Cellerant is pursuing its own efforts and is also exploring external technologies in order to develop ADCs with broader therapeutic windows.
Cellerant also has development efforts focused on the discovery, characterization, and development of antibodies against CSC antigens. Our knowledge and experience of normal blood cell biology has been applied to the development of therapeutic antibodies directed at blood cancer cell targets that are not present on normal blood cells to minimize side effects associated with toxicity to normal cells, which are often experienced with other therapeutics. Using gene expression arrays of highly purified populations of normal cells and CSCs, Cellerant has identified targets specific to AML CSCs.
Current cancer indications
Cellerant continues to leverage extensive experience in cell biology and antibody generation and screening to produce novel therapeutic antibodies having high selectivity for blood cell cancers and other disease targets of interest.
Cellerant is committed to discovering and developing novel antibody therapies for leukemia, myeloma, and other blood cancers. AML and high-risk MDS arise from myeloid lineage of blood cells with abnormal properties, characterized by rapid growth, arrested development, and accumulation in the bone marrow that interferes with normal blood cell production. In the U.S. in 2015, it is estimated that 20,830 new AML cases will be diagnosed and that more than 10,000 patients will die from the disease (American Cancer Society). More than 11,000 new MDS cases are diagnosed in the U.S. each year (SEER, National Cancer Institute). The current standard of care for these diseases is ineffective, resulting in an average 5-year survival rate for AML patients of only 25.4%, and survival is much worse (5.6%) for patients older than 65 years (SEER, National Cancer Institute). MM is a cancer of the blood plasma cells. An estimated 26,850 new cases of MM will be diagnosed and more than 11,240 will die from the disease in the U.S. in 2015 (American Cancer Society). Current therapies provide a 5-year survival rate of about 47% (SEER, National Cancer Institute). Better treatments are needed to improve the survival rates for these cancers.
Cellerant also has drug discovery efforts ongoing to identify novel targets for tumors associated with Neurofibromatosis (NF). NF is a neurological disorder with Neurofibromatosis Type 1 (NF1) being the most common. NF1 is caused by a mutation in a single gene, neurofibromin, and occurs in one in every 3,000 newborns (Children's Tumor Foundation). NF1 patients will commonly develop neurofibroma located on the skin (cutaneous) and/or internally (plexiform). These patients may also develop more aggressive and deadly malignant peripheral nerve sheath tumors, which currently have no viable treatment. Standard of care for NF1 patients with tumors includes surgery, radiation, and chemotherapy, which have only a modest effect in managing the disease. Cellerant is profiling various tumors and tumor cell types associated with NF1 disease to develop an antibody-based therapy that should be more specific and with fewer side effects to help alleviate the tumor burden in patients with NF1.