The most important lines of cancer research are those that might lead to therapies that can be applied to many (or even all) types of cancer with little adjustment of delivery or payload. This requires a mechanism that is present in most or all cancers, and which is essential to the cancer, such that cancer cells cannot just evolve away from using it in response to treatment. At present only a few areas of focus offer this potential, such as interference in telomere lengthening. Here, researchers describe a novel approach that seems to have a broad potential to treat the majority of cancers. It involves the delivery of a molecule that encourages T cells to bind to specific surface molecules that are characteristic of cancer cells, but which normally bind poorly and have thus been ignored as a possible target in the past.
Bispecific antibodies and chimeric antigen receptor T cells (CAR T) potently reduce tumor burden in B cell-related malignancies. Both trigger T cell-mediated killing of cancer cells by targeting a cell-surface cancer antigen using modified antibodies. However, applying this therapeutic strategy to the majority of cancer types, particularly solid cancers, is limited by a lack of safe targetable protein antigens.
Many cell-surface cancer antigens are not proteins but rather complex carbohydrates and are termed "tumor-associated carbohydrate antigens" (TACAs). Two well-described TACAs are β1,6GlcNAc-branched N-glycans and the Tn antigen, the latter an abnormally truncated O-glycan. As both markers and drivers of diverse cancers, β1,6-branching and Tn antigen provide excellent targets for antigen-specific immunotherapies. However, anti-glycan antibodies typically have affinities 1,000-100,000-fold lower than antibodies to peptide antigens. This is due to higher flexibility of glycans than peptides, absence of T cell help to B cells from lack of major histocompatibility complex (MHC) presentation of pure glycans, and attachment of glycans to a vast array of different proteins/lipids resulting in a non-uniform antigen.
The inability to generate an antibody to β1,6-branching and effective antibodies to pure Tn antigen has prevented effective targeting of these well-established tumor-associated antigens. To address this issue, we envisioned a class of immunotherapeutics that utilize sugar-binding proteins (lectins) that have well-established specificity, rather than antibodies, to target glycan antigens. We have termed this "glycan-dependent T cell recruiter" (GlyTR, pronounced "glitter"). GlyTR bispecific proteins fuse a carbohydrate-recognition domain (CRD) from a lectin to a single-chain variable fragment (scFv) from an antibody targeting CD3. Lectins utilize high binding avidity (velcro-like binding) to achieve specificity for glycan targets. This is in distinction to antibodies, where high affinity (key-lock binding) achieves specificity.
We developed GlyTR1 and GlyTR2 to bind immunosuppressive β1,6GlcNAc-branched N-glycans or multiple TACAs, respectively. GlyTR1 and GlyTR2 overcome immunosuppressive mechanisms in the tumor microenvironment and trigger target-density-dependent T cell-mediated pan-cancer killing, yet they lack toxicity in mice with human-like TACA expression. Thus density-dependent lectin binding to TACAs provides highly potent and safe pan-cancer immunotherapeutics.
Link: https://doi.org/10.1016/j.cell.2025.09.001
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