Peptide neo-epitope (PNE) (specifically the LLE-containing variant) on adapter molecules (PNE)

The LLE neo-epitope is a synthetic or non-human peptide sequence, often derived from the yeast transcription factor GCN4, that serves as a universal target for switchable Chimeric Antigen Receptor T-cell (sCAR-T) therapies. In this modular platform, the CAR-T cells are engineered to recognize the LLE peptide tag instead of a specific tumor-associated antigen. The specificity of the treatment is provided by a 'switch' or 'adapter' molecule, which is a tumor-targeting ligand (such as a Fab fragment) conjugated to the LLE epitope. In some configurations, the adapter is biotinylated via the LLE tag to facilitate site-specific conjugation or analytical tracking. This technology, primarily developed by Calibr (a division of Scripps Research), aims to overcome the safety and flexibility limitations of traditional CAR-T therapies. By decoupling the antigen recognition from the T-cell activation, clinicians can control the intensity of the immune response through the dosing of the adapter molecule, potentially mitigating severe side effects like cytokine release syndrome. Furthermore, the platform allows for the targeting of multiple antigens sequentially or simultaneously using a single CAR-T cell product, providing a versatile tool for treating heterogeneous or relapsed cancers. Clinical candidates utilizing this target include CLBR001 (the CAR-T cell) in combination with various antigen-specific switches like SWI019 for B-cell malignancies.

Other names

LLE neo-epitopeLLE tagPeptide neo-epitopeSwitchable CAR-T target epitopeGCN4-derived peptide tagLLE-biotin adapter target

The target functions as a universal docking site in a switchable Chimeric Antigen Receptor T-cell (sCAR-T) system. The CAR-T cell (e.g., CLBR001) is engineered to express a receptor that specifically recognizes the LLE neo-epitope rather than a native tumor antigen. A bifunctional adapter molecule (the 'switch') is administered, which consists of a tumor-targeting moiety (such as an anti-CD19 or anti-BCMA Fab fragment) conjugated to the LLE neo-epitope. When the adapter binds to the tumor cell, it presents the LLE epitope to the CAR-T cells, triggering their activation, proliferation, and subsequent lysis of the tumor cell. This modular approach allows for dose-titratable control of CAR-T activity and the ability to redirect the same CAR-T cell population against different antigens by switching the adapter molecule.