Shattuck Labs Showcases Preclinical Data for Gamma Delta T-Cell Engager (GADLEN) Platform at AACR
By Alex Keown
March 20, 2023
Shattuck Labs CD20-targeted GADLEN platform demonstrated preclinical proof of concept of rapid B cell depletion in humanized mice and non-human primates. If all goes according to plan, the company aims to advance the platform into human testing for cancer and autoimmune diseases.
Based in Durham, N.C., Shattuck will present preclinical data from the Gamma Delta T-Cell Engager (GADLEN) Platform at the 2023 American Association for Cancer Research (AACR) Annual Meeting in Orlando. The company’s abstract “Rapid Serial Killing of Target Cells by Vγ9Vδ2 T Cells in Cynomolgus Macaques and Humanized Mice Treated with a CD20-Directed Heterodimeric Butyrophilin 2A1/3A1 Fusion Protein” will highlight the potential of GADLEN for B cell malignancies.
Taylor Schreiber, Chief Executive Officer of Shattuck Labs, said the company’s CD20-targeted GADLEN platform was able to direct Vγ9Vδ2 T cells to “serially kill greater than 99% of human B cells” in a humanized mouse model.
“These data led to the first study of a GADLEN compound in non-human primates, where once again treatment with a CD20-targeted GADLEN directed low frequencies of endogenous Vγ9Vδ2 T cells to eliminate CD20 positive B cells with a rapid kinetic,” Schreiber said in a statement. “Importantly, the GADLEN compound was well tolerated in non-human primates up to the highest administered dose of 25 mg/kg, without evidence of cytokine release syndrome or other toxicities, potentially providing differentiation from CD3-directed T cell engagers.”
Shattuck’s bispecific GADLEN compound contains heterodimeric BTN2A1 and BTN3A1 extracellular domains that are fused by an inert Fc linker to a scFv domain targeting CD20 tumor-antigens. GADLEN demonstrated an ability to rapidly deplete human and cynomolgus B cells in a dose-dependent manner.
The presence of gamma delta T cells within cancer tumors is correlated with increased survival in cancer patients, yet, according to the company, these cells only represent about 2% to 5% of the total T cell population. Gamma delta T cells are activated by a complex of heterodimerized butyrophilin proteins. The use of gamma delta T cells is a novel approach to treat cancer, as it presents an “opportunity to treat checkpoint refractory patients with a fundamentally new therapeutic modality,” Shattuck Labs notes on its website.
Shattuck’s GADLEN compounds consist of two distinct fusion protein chains, with an engineered Fc linker domain that facilitates heterodimerization between the two chains. Each of these chains includes an extracellular domain of a specific butyrophilin protein, which is linked to tumor antigen-specific single-chain antibody fragments, the company said. These two chains come together to form a functional butyrophilin heterodimer that activates a specific gamma delta T cell receptor.
“These data underlie our enthusiasm to advance a GADLEN product candidate into the clinic designed for the treatment of antibody-mediated autoimmune diseases,” Schreiber said.
Beyond its GADLEN platform, Shattuck Labs is also developing its ARC (Agonist Redirected Checkpoint) platform for cancer. The ARC platform has been used to create more than 400 unique therapeutic candidates for the treatment of cancer and autoimmune disease, according to the company.
The company’s ARC molecule combines a checkpoint inhibitor with a TNF ligand to achieve a hexameric structure. Shattuck Labs said this offers an advantage over antibody-based therapeutics through “superior” tumor rejection.
- About the Author
- Latest Posts
Alex Keown is a freelance journalist who writes about a variety of subjects including the pharma, biotech, and life science industries. Prior to freelancing, Alex has served as a staff writer and editor for several publications.
