Treatment of non-resectable recurrent/metastatic solid cancers is currently palliative only and there is anurgent unmet need for novel mechanisms of action and additional paradigm shifting therapeutic options. Antigen-targeting cancer immunotherapies such as bi-specific antibodies (eg Bi-specific T cell engager or BiTE's) providea unique approach for cancer immunotherapy. However, applying this therapeutic tactic to solid cancers hasbeen restricted by a limited number of protein antigens safe for targeting. Moreover, even if safe cell-surfaceantigens are identified, different bi-specific antibodies will likely be needed for each different antigen/cancer. Thiswould greatly increase development time and costs. Thus, there remains a great need for additional safe antigen-specific immunotherapies, particularly for those with refractory/metastatic solid cancers who have fewtherapeutic options. Many cell surface cancer-specific antigens are not proteins but rather complexcarbohydrates that have limited or no expression in normal tissues. For example, β1,6GlcNAc-branched N-glycans constitute a small subset of the complex-type N-glycans expressed at the surface of normal human cellsbut are markedly up-regulated in diverse solid cancers by driver mutations in the receptor tyrosinekinase/RAS/phosphoinositide-3-kinase(PI3K) signaling pathway. Aberrant over-expression of β1,6GlcNAc-branched N-glycans in solid tumors drives RTK signaling, tumor growth, motility, invasion, and metastasis. Asboth a marker and driver of many diverse cancers, β1,6 GlcNAc-branched N-glycans provide an excellent targetfor antigen-specific immunotherapies. However, an antibody to β1,6GlcNAc-branched N-glycans has never beengenerated. To address this issue, we generated a novel class of immunotherapeutics that readily target abnormalglycan antigens with high specificity. We have termed this technology "Glycan-dependent T cell Recruiter'(GlyTR, pronounced "glitter'). With funding from the Biden Cancer Moonshot program of the National CancerInstitute, we developed and optimized the GlyTR1 bi-specific protein that binds both β1,6GlcNAc-branched N-glycans and CD3 in T cells. The GlyTR1 bi-specific protein induces T cell-dependent killing of a wide diversity ofsolid cancers in vitro and in vivo with EC50's as low as ~50 femtomolar, yet does not kill normal cells or trigger"on-target, off-cancer" toxicity in humanized mouse models. GlyTR1 is undergoing late-stage IND-enablingstudies and upon FDA approval, the UC Irvine Cancer Center will perform a dose-escalation Phase 1 clinicaltrial in relapsed/metastatic solid cancer. However, as GlyTR1 has a short half-life of ~2.5hrs and requiresconstant intravenous infusion, herein we propose to develop a longer half-life version of GlyTR1. We alsopropose to examine for potential additive/synergistic activity with checkpoint inhibitors. Data from thisproposal will be used to inform future clinical trials following confirmation of safety of GlyTR1 in our Phase 1 trial,namely whether a longer half-life GlyTR1 and/or co-treatment with checkpoint inhibitors should be pursued.
Public Health Relevance Statement: Project Narrative
Directing the immune system to kill cancer cells is a highly potent way of treating cancer.
Abnormal addition of carbohydrates to proteins is a near universal feature of cancer, however
current immunotherapies cannot readily target these. Here we propose to further develop a novel
technology that directs immune cells to kill cancer cells based on expression of altered
carbohydrates.
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