26-biotech-biopharm-cancer.pptx

Biopharmaceuticals and Cancer treatment 1 Learning objectives • Learn about the molecular targets of Biopharmaceuticals to treat cancer. • Learn about the types of Biopharmaceuticals which are used to treat cancer; mAbs and small molecules. 2 Why are we still not able to beat cancer? • Why are...

Biopharmaceuticals and Cancer treatment 1 Learning objectives • Learn about the molecular targets of Biopharmaceuticals to treat cancer. • Learn about the types of Biopharmaceuticals which are used to treat cancer; mAbs and small molecules. 2 Why are we still not able to beat cancer? • Why are we still not able to beat lifethreatening diseases such as cancer with our current arsenal of drugs? Causes of failure can be summarized as Follows : (1) The active compound never reaches the target site, because it is rapidly eliminated intact from 3 (2) Only a small fraction of the drug reaches the target site. By far the largest fraction of the drug is distributed over non-target organs, where they exert side effects; in other words, Accumulation of the drug at the target site is the exception and not the rule. (3) Many drug molecules (in particular high MW and hydrophilic molecules, i.e., many therapeutic proteins) do not enter cells easily. This poses a problem if intracellular delivery is required for their therapeutic activity. 4 • Attempts are made to increase the therapeutic index of drugs through drug targeting: (1)by specific delivery of the active compound to its site of action, (2) to keep it there until it has been inactivated and detoxified. 5 The Approach and the Target • A significant amount of biopharmaceuticals, such as monoclonal antibodies (MAbs), non-antibody proteins and small molecules, have been developed and applied to treat various cancers. • Biopharmaceuticals target the following for an effective elimination of cancer: 1) Genetically abnormal molecules (e.g. antigens), or 2) Core pathways 6 1) Abnormal molecules (Antigenes) • Cluster of differentiation (CD): a well-studied antigen that represents different groups of glycoproteins and carbohydrates expressing on the surface of cancer cells. The hematopoietic CD20, CD30, CD33 and CD52 expressed by non-Hodgkin lymphoma, Hodgkin lymphoma, acute myelogenous leukemia, and chronic lymphocytic leukemia, respectively, are the excellent antigens to bind to anti-CD recombinant antibodies. • Growth factors: supports the formation of microvasculature. Examples include: vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), integrin, receptor tyrosine-protein kinase, Epidermal growth factor receptor (EGFR). 7 2) Core pathways • Glycolysis: target enzyme for biopharmaceuticals is Pyruvate kinase which is the terminal enzyme of the glycolysis pathway, which regulates intracellular energy balance and major control element in the pathway. • Signal transduction pathways: examples include tyrosin kinases (e.g. phosphatidylinositide 3-kinases) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). 8 MAbs as a treatment choice For cancer 9 Monocloncal Antibodies (MAbs) (Immunotherapy) * Antibodies can kill cancer cells directly by : 1) inhibiting signaling, reducing proliferation, inducing apoptosis, 2) inducing immune-mediated phagocytosis, complement-dependent cytotoxicity (CDC) 3) ablating vascular and stromal cells via vessel receptor antagonism * indirectly by: 1) delivering medicine, radiation or cytotoxin (slide 14) 2) activating T cells 10 Molecular targets of MAbs • 50% mAbs targeting different CD antigens to treat non-hodgkin’s lymphoma, chronic lymphocytic leukemia, lymphoma and leukemia; • 19% mAbs targeting HER2 antigen to treat HER2-positive metastatic breast cancer and gastroesophageal cancer 11 • MAbs used to treat cancer in Royal Hospital and SQUH: → Rituximab (Rituxan in USA and Mabthera in Asia and Europe) – Anti-CD20 = non-Hodgkin lymphoma (NHL); chronic lymphocytic leukemia (CLL). → Trastuzumab (Herceptin) - Target HER2 = breast cancer treatment. → Panitumumab (Vectibix) – Target epidermal growth factor receptor (EGFR) = colorectal cancer. 12 * Challenges and potential problems while targeting Tumors: - Tumor heterogeneity: tumors may have many subpopulations of cells. - Antigen shedding: antigens may get released which can interact outside target area. - Antigen modulation: a cancer cell can create antigens which are not recognized by the MAb molecule. ► One solution: use of a mixture of MAbs to target different types of antigens expressed on the surface of the cancer cell Learning outcomes • There are decent number of biopharmaceuticals available in Oman and the int’l market. Most of these preparations are giving by injection through the skin. • Biopharmaceuticals are now becoming a potential treatment for cancer because of specificity in targeting cancer cells with various targeting options. • MAbs are the most common type of biopharmaceutical available to treat cancer. 14