GLAAS® and ZVex® are our proprietary discovery platforms designed to activate and expand the immune system’s natural ability to create tumor-specific cytotoxic T cells (CTLs) in vivo. In addition to oncology, these novel technology platforms hold promise for applications in the fields of infectious and allergic diseases, and have also been the source of several partnered programs.
We have designed our product candidates to have the potential to target multiple types of cancers.
A Novel in vivo Discovery Platform to Boost Immune Responses
GLAAS, which stands for “GLA Adjuvant Systems,” is a discovery platform that is designed to work in vivo and is based on a synthetic small molecule, Glucopyranosyl Lipid A (GLA). GLA selectively binds to the TLR4 receptor to cause potent activation of DCs. We have been using GLA to treat cancer patients in two different ways.
First, when GLA is accompanied by a tumor antigen and injected into a patient, the combination is taken up by the DCs and leads to the production and expansion of immune cells called CD4 helper T cells. Similar to CTLs, these CD4 T cells will be specific to a tumor antigen, but unlike CTLs, they generally cannot kill antigen-bearing tumor cells. They do, however, play a key role in helping to boost the anti-tumor immune response by: (1) expanding the number and improving the function of existing CTLs that are specific to the same tumor antigen; and (2) providing help to other immune cells, including B lymphocytes that are precursors to antibodies and natural killer (NK) cells that are also important in the overall anti-tumor immune response.
We leverage the GLAAS platform via intratumoral immune activation, an approach that is designed to activate the immune system in the tumor microenvironment. Instead of targeting specific tumor antigens, this approach relies on endogenous antigens (including neoantigens) present in the tumor. In this case, we use a specific formulation of GLA as our G100 product candidate, which is injected directly into the tumor, and neighboring GLA-activated DCs are expected to capture the diverse set of released antigens and generate a broad and varied immune response.
The GLAAS Difference
- A strong immune response whereby DCs are activated and can express antigens, as well as secrete a number of inflammatory cytokines that lead to the activation of other immune cells, such as NK cells.
- When accompanied by an antigen in protein form, generation of a strong, antigen-specific adaptive immune response characterized by CD4 T cells.
- Reversal of allergic immune response to a normal immune state.
A Novel in vivo Discovery Platform to Generate Targeted CTLs
ZVex is a discovery platform that uses a first-in-class vector to generate product candidates designed to create CTLs in vivo. A primary function of CTLs is the selective recognition and destruction of tumor cells. The ZVex vector is a delivery system based on a hybrid, re-engineered virus designed to carry genetic information of a tumor antigen(s) (in whole or selected epitopes, including neo-epitopes) safely and selectively to dendritic cells (DCs) in the skin. We believe DCs are the most important immune cells to target because they initiate the specific immune response that generates CTLs to kill the tumor.
When a ZVex product candidate is injected into a cancer patient, the vector is designed to interact only with DCs and to deliver the tumor antigen in the form of RNA. The DC then process the RNA into a protein, splits the protein and presents the protein fragments outside the cell to neighboring CD8 T cells, which are precursors to CTLs. This process activates the CD8 T cell and causes it to divide, creating millions of CTLs to kill tumor cells that bear that specific tumor antigen, including neoantigens.
The ZVex system is designed with a variety of features that may offer an improved approach to generating an immune response. In addition, because ZVex product candidates have the potential to carry the genetic material of different tumor antigens, as well as immunostimulatory molecules, we can design them to target multiple types of cancers.
ZVex originated from underlying discoveries made by one of Immune Design’s founders and Nobel laureate, David Baltimore, Ph.D.
The ZVex Difference
- Selectivity for DCs intended to generate the maximum CTL response.
- Capacity for substantial genetic payload supports multiple tumor antigens or a combination of tumor antigens and other immune stimulatory molecules, such as checkpoint inhibitors.
- No prior immunity to ZVex vectors allows for multiple administrations and therefore increases the potential for therapeutic benefit.
- Integration deficiency of ZVex vectors makes them safer for patients.
- Platform to generate product candidates for multiple indications because each ZVex product candidate can target a different tumor.
ZVex® + GLAAS®
A Synergistic Prime-Boost Approach to Cancer Immunotherapy
An exciting aspect of the Immune Design discovery platforms is the potential mechanistical synergy of ZVex + GLAAS.
ZVex and GLAAS are designed to combine and yield a more potent immune response called a “heterologous prime-boost”. The ZVex vector is designed to to prime the immune system by triggering the generation of cytotoxic T lymphocytes (CTLs) while GLAAS, through activation of CD4s, works to boost the immune response by expanding and enhancing the function of CTLs and other anti-tumor mechanisms.
CMB305 is the first combination product candidate that will combine ZVex- and GLAAS-derived agents.