To direct T cells toward carbohydrate antigens, Zhou et al. devised T cell engagers called GlyTRs by linking a glycan-binding lectin to an anti-CD3 scFv. GlyTRs bound a diverse range of malignant cells/tissues, and mediated killing by T cells in coculture, dependent on binding avidity (influenced by binder multimerization and target density). GlyTRs enabled TIL cytotoxicity in organoid and patient-derived tumor models, and controlled metastatic tumor lines in humanized NSG mice. Injected i.v. into mice, GlyTRs accumulated in the liver and spleen without toxicity. Lectin binding also counteracted glycan-mediated immunosuppression.
Contributed by Alex Najibi
ABSTRACT: Bispecific antibodies and chimeric antigen receptor T cells are some of the most potent cancer immunotherapeutics in clinical use, yet most cancers remain poorly targetable. High-affinity antibodies required to maximize killing detect low antigen expression in normal tissue, risking "on-target, off-cancer" toxicity. This compels identification of cancer-restricted cell-surface protein antigens, which are rare. Tumor-associated carbohydrate antigens (TACAs) are the most abundant and widespread cancer antigens known but are poorly targetable by antibodies. Here, we describe glycan-dependent T cell recruiter (GlyTR) pan-cancer immunotherapeutics that utilize high-avidity "velcro-like" lectin binding to kill cells with high but not low TACA expression. GlyTR1 and GlyTR2 bind immunosuppressive _1,6GlcNAc-branched N-glycans or multiple TACAs (Tn, sialyl-Tn, LacDiNAc, and GD2), respectively, 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. Density-dependent lectin binding to TACAs provides highly potent and safe pan-cancer immunotherapeutics.
Author Info: (1) Department of Neurology, University of California, Irvine, Irvine, CA, USA; GlyTR Therapeutics Inc., Irvine, CA, USA. (2) Department of Neurology, University of California, Irv
Author Info: (1) Department of Neurology, University of California, Irvine, Irvine, CA, USA; GlyTR Therapeutics Inc., Irvine, CA, USA. (2) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (3) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (4) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (5) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (6) Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA, USA. (7) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (8) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (9) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (10) Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA, USA. (11) Department of Neurology, University of California, Irvine, Irvine, CA, USA; Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA. Electronic address: mdemetri@uci.edu.
