Gamma Delta T Cell Engager (GADLENTM) platform
Design and Structure
About the GADLEN Platfrom
Gamma delta T cells represent approximately 2% to 5% of the total T cell population, and their presence within tumors is strongly correlated with increased survival in cancer patients. Unlike alpha beta T cells which recognize tumor antigens presented on major histocompatibility complex molecules, gamma delta T cells are activated by a newly identified, tissue-specific complex of heterodimerized butyrophilin proteins. The therapeutic utilization of gamma delta T cells represents a novel approach for the treatment of cancer, as it presents an opportunity to treat checkpoint refractory patients with a fundamentally new therapeutic modality.
We have leveraged our in-house expertise in protein engineering and intellectual property to build a novel Gamma Delta T Cell Engager, or GADLEN, platform to harness gamma delta T cells for the treatment of cancer. This is Shattuck’s second, wholly owned, platform to solve a biological problem by creating a therapeutic that matches the native structure of the target.
GADLEN compounds are comprised of two distinct fusion protein chains, with an engineered Fc linker domain that facilitates heterodimerization between the two chains. Each fusion protein chain consists of an extracellular domain of a specific butyrophilin protein on one side which are linked to tumor antigen specific single chain antibody fragments on the opposite side. The two chains heterodimerize to form a functional butyrophilin heterodimer that activates a specific gamma delta T cell receptor.
GADLEN compounds are designed to facilitate the targeting of specific gamma delta T cells to tumor cells expressing a defined antigen. We believe our GADLEN platform offers a novel approach to the treatment of cancer.
Mechanism of Action For The Gadlen Platform
- GADLEN compounds bind and activate γδ T cell receptor via the butyrophilin (BTN) heterodimer domain
- Stimulation of γδ T cell receptor leads to γδ T cell proliferation, activation, and clonal expansion
- Compounds have tumor targeted scFv domain, which allows for specific and directed γδ T cell killing of targeted tumor cell targets
Key Attributes of the Gadlen Platform
- GADLEN compounds activate target cells via a complex of heterodimerized butyrophilin proteins and do not rely on the classical antigen presentation on major histocompatibility complex (MHC 1) like alpha/beta T Cells
- GADLEN compounds have the potential to target tumors that have developed acquired resistance to immune checkpoint inhibition
- GADLEN compounds combine a butyrophylin heterodimer and tumor antigen targeting scFv through an IgG Fc linker
- The unique structural characteristic of these compounds allows targeting of specific tissue resident T cell populations
- Each butrophylin heterodimer and antigen targeting scFv in the GADLEN can be substituted, enabling a plug and play approach to producing thousands of potential therapeutic combinations
Shattuck anticipates announcing a lead candidate from the GADLEN platform in 2021.