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Extended half-life GlyTR1 combined with checkpoint blockade for Cancer Immunotherapy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R42CA285234-01
Agency Tracking Number: R42CA285234
Amount: $400,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 102
Solicitation Number: PA22-178
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-09-21
Award End Date (Contract End Date): 2024-08-31
Small Business Information
Irvine, CA 92617-3206
United States
DUNS: 080209701
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (949) 824-9775
Business Contact
Phone: (916) 612-9988
Research Institution
IRVINE, CA 92697-0001
United States

 Nonprofit College or University

AbstractTreatment of non-resectable recurrent/metastatic solid cancers is currently palliative only and there is an
urgent 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) provide
a unique approach for cancer immunotherapy. However, applying this therapeutic tactic to solid cancers has
been restricted by a limited number of protein antigens safe for targeting. Moreover, even if safe cell-surface
antigens are identified, different bi-specific antibodies will likely be needed for each different antigen/cancer. This
would 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 few
therapeutic options. Many cell surface cancer-specific antigens are not proteins but rather complex
carbohydrates 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 cells
but are markedly up-regulated in diverse solid cancers by driver mutations in the receptor tyrosine
kinase/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. As
both a marker and driver of many diverse cancers, β1,6 GlcNAc-branched N-glycans provide an excellent target
for antigen-specific immunotherapies. However, an antibody to β1,6GlcNAc-branched N-glycans has never been
generated. To address this issue, we generated a novel class of immunotherapeutics that readily target abnormal
glycan 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 Cancer
Institute, 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 of
solid 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-enabling
studies and upon FDA approval, the UC Irvine Cancer Center will perform a dose-escalation Phase 1 clinical
trial in relapsed/metastatic solid cancer. However, as GlyTR1 has a short half-life of ~2.5hrs and requires
constant intravenous infusion, herein we propose to develop a longer half-life version of GlyTR1. We also
propose to examine for potential additive/synergistic activity with checkpoint inhibitors. Data from this
proposal 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.

* Information listed above is at the time of submission. *

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