Active Immune Therapy
Background on the Immune System
It is helpful to know some facts about the immune system to better understand how and why Memgen's active immune therapy technology addresses the treatment of a wide variety of cancers. The immune system is made up of several components that work together to ward off infection. Of these components, the most critical is a group of white blood cells known as lymphocytes. There are two types of lymphocytes, T lymphocytes and B lymphocytes. Everyone has a fixed number of T lymphocytes, which last a lifetime; B lymphocytes are manufactured continually by bone marrow, and their life spans vary.
In a healthy immune system, B lymphocytes and T lymphocytes work together to fight and eliminate damaging agents (antigens), such as bacteria, viruses, fungi, cancerous cells, or other toxic substances. The primary task of T lymphocytes is to recognize foreign antigens and destroy cells that have certain antigens bound to them, although they may also enlist other T cells to do the work for them. B lymphocytes capture foreign proteins floating inside the body and present them to T cells for further processing. B lymphocytes also produce antibodies, molecules that bind to foreign substances and destroy them.
Memgen's Active Immune Therapy Approach
Among the lymphocytes swarming within someone's immune system are activated T lymphocytes; that is, T lymphocytes that have detected a foreign antigen. Once identification of an antigen has been made, T lymphocytes communicate with B lymphocytes by making a protein, called CD40 ligand or CD154, on their surface that binds specifically to a receptor called CD40 on the B lymphocytes.
In order for Memgen to use some version of CD154 molecules therapeutically to interact with cancerous B cells, several things need to happen. Since naturally occurring human CD154 molecules are poorly expressed in human CD40+ B lymphocytes, Memgen has rebuilt the human version of the molecule. This reengineered molecule, named ISF35, is designed to maximize its expression in human B lymphocytes. Because of this modification, the ISF35 molecule is superior to naturally occurring human CD154 in its ability to bind to its receptor CD40 and to activate recipient (cancerous) B lymphocytes.
To deliver the ISF35 molecule to target malignant B lymphocytes, Memgen uses a replication defective type 5 adenovirus. The adenovirus infects the leukemic cells, resulting in the stable expression of the ISF35 molecule on the cell surface. The adenoviral proteins trigger the immune system to attack infected malignant cells, and ISF35 augments this response, resulting in a localized full-force reaction against the treated cells. When the triggering antigen (adenoviral protein) disappears because the carrier adenovirus does not replicate, the treated cells undergo spontaneous apoptosis. In this manner, ISF35 results in the rapid reduction of circulating and lymph node-bound leukemic cells, the up-regulation of pro-apoptotic proteins sensitizing these cells to standard treatments, and the generation of anti-leukemic immune responses that may have long term impact on disease progression. The adenovirus, containing the ISF35 molecule, can be used to infect leukemic cells ex vivo or by direct injection into tumor beds.
