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

Award Number: R42CA285234
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,085,460 )
2025	2025	GLYTR THERAPEUTICS, INC.	5151 CALIFORNIA AVE	IRVINE	CA	92617	ORANGE	USA	Cancer Treatment Research	001	3	8/22/2025	NON-COMPETING CONTINUATION	$1,085,460
2025	2023	GLYTR THERAPEUTICS, INC.	5151 CALIFORNIA AVE	IRVINE	CA	92617	ORANGE	USA	Cancer Treatment Research	000	1	2/3/2025	NEW	$0
														Subtotal = $1,085,460

Issue Date FY: 2024 ( Subtotal = $908,910 )
2024	2024	GLYTR THERAPEUTICS, INC.	5151 CALIFORNIA AVE	IRVINE	CA	92617	ORANGE	USA	Cancer Treatment Research	001	2	8/29/2024	EXTENSION WITH OR WITHOUT FUNDS	$908,910
2024	2023	GLYTR THERAPEUTICS, INC.	5151 CALIFORNIA AVE	IRVINE	CA	92617	ORANGE	USA	Cancer Treatment Research	000	1	10/12/2023	NEW	$0
														Subtotal = $908,910

Issue Date FY: 2023 ( Subtotal = $400,000 )
2023	2023	GLYTR THERAPEUTICS, INC.	5151 CALIFORNIA AVE	IRVINE	CA	92617	ORANGE	USA	Cancer Treatment Research	000	1	9/20/2023	NEW	$400,000
														Subtotal = $400,000

Grand Total All Awards = $2,394,370

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

Award Number: R42CA285234

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/21/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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