Aptamer Drug Conjugate (Apta-DC)
Systematic evolution of ligands by exponential enrichment (SELEX) is a well-established and efficient technology for the generation of oligonucleotides with a high target affinity. These SELEX-derived single stranded DNA and RNA molecules, called aptamers, were selected against various targets, such as proteins, cells, microorganisms, chemical compounds - etc. They have a great potential in the use as novel antibodies, in cancer theragnostics and in biomedical research. Furthermore, when the aptamer conjugated with small molecule drug, this combination is expected to bring together the benefits of highly potent drugs on the one hand and selective binders of specific disease target on the other hand. When it comes to cancer therapy, these loaded aptamer drug pairs are expected to selectively deliver lethal cargoes to tumor cells and provide sustained clinical benefit to pre-selected cancer patients while, at the same time, minimizing systemic toxicity.
Target Disease : pancreatic cancer
Status : Preclinical
Apta-12 consists of AS1411*, a clinically tested DNA aptamer against surface nucleolin found in many cancer cells, and activated form of gemcitabine (Gemzar®)- dFdCMP. Unlike ADCs (antibody drug conjugates) or SMDCs (small molecule drug conjugates), which require ‘linker’ conjugation of the cytotoxic payload to the drug, Apta-12 is created by replacing a thymidine molecule in AS1411 with a gemcitabine molecule, during the single-step solid phase synthesis.
Nucleolin is constantly and abundantly expressed on the cell surface of tumor cells where it serves as a binding protein for variety of ligands implicated in cancer growth and angiogenesis. Apta-12 binds to nucleolin on the outside of the cancer cell, is taken up by the cells, and released inside. Once inside the cancer cell, Apta-12 also binds to nucleolin that is present in the nucleus of the cancer cell. This process triggers cancer cell killing. Meanwhile, cancer killing drug is released to do additional damage to the cell. This dual mode of action makes Apta-12, a very potent drug to cancer cells. In fact, lab experiments have shown that Apta-12 can be 10 - 1,000 times more active than nucleolin modulator alone.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy. It is the fourth leading cause of cancer-related death in the United States and second only to colorectal cancer as a cause of digestive cancer-related death. Surgical resection is the only potentially curative treatment. Unfortunately, because of the late presentation, only 15-20% of patients are candidates for surgical intervention. Furthermore, prognosis is poor, even after a complete resection. Five-year survival after pancreaticoduodenectomy is ~25-30% for node-negative and 10% for node-positive disease.
(Am J Gastroenterol advance online publication, 31 January 2017; doi: 10.1038/ajg.2016.610)
Target Disease : AML
Status : Preclinical
Apta-16 is a potent dual action anticancer therapy which is consist of aptamer and blood cancer drug. The synergistic effect of conjugated therapy, Apta-16, enable to overcome the drug resistance of cancer and narrow therapeutic index.
Acute myeloid leukemia (AML) is a form of cancer that is characterized by infiltration of the bone marrow, blood, and other tissues by proliferative, clonal, abnormally differentiated, and occasionally poorly differentiated cells of the hematopoietic system. Although it was incurable 50 years ago, AML is now cured in 35 to 40% of adult patients who are 60 years of age or younger and in 5 to 15% of patients who are older than 60 years of age. The outcome in older patients who are unable to receive intensive chemotherapy without unacceptable side effects remains dismal, with a median survival of only 5 to 10 months. (N. Engl. J. Med. 2015; 373:1136-1152)