# N-glycosylation and Immunotherapy for cancer

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $673,731

## Abstract

Project Summary
For decades, the treatment of cancer has relied on surgical resection, chemotherapy and/or radiotherapy.
Recently, a number of immune based therapies have provided promising new approaches for cancer treatment.
These include checkpoint inhibitors that block T cell suppression (eg anti-PD-1), bi-specific antibodies that
cross-link T cells to cancer cells (eg Bi-specific T cell engagers – BiTE) and T cells engineered to express
antigen receptors specific to cancer cells (eg Chimeric Antigen Receptor T cells or CAR T). All three
approaches induce T cell mediated killing of cancer cells. However, widespread development of bi-specific
antibodies and CAR T cells is limited by the small number of known cell-surface proteins that are sufficiently
specific to cancer to safely allow targeting by antibodies. This is particularly true for solid cancers, where unlike
hematopoietic malignancies, loss of healthy cells cannot be readily replenished by stem cell progenitors. A
solution to this issue is to target cancer specific glycan antigens rather than protein antigens. Indeed, altered
glycosylation is a near universal feature of cancer and represent the most abundant and widely expressed cell
surface cancer antigens, while also having limited or no expression in normal tissue. However, generation of
monoclonal antibodies specific to complex carbohydrates has proven to be very challenging, greatly limiting
their usefulness as targets for cancer immunotherapy. Here we propose to address these issues and
develop a novel class of immunotherapeutics that target an N-linked carbohydrate antigen common to
the vast majority of solid and hematopoietic cancers. We have termed these molecules as Glycan-
dependent T cell Recruiter (GlyTR) technology. Critically, GlyTR technology does not utilize antibodies to
target carbohydrate cancer antigens. Preliminary data demonstrates that the GlyTR bi-specific protein 1)
specifically bound to both human CD3 and its N-glycan target, 2) robustly activated T cells only in the presence
of cancer cells, 3) induced T cell dependent killing of cancer cells with an EC50 as low as 5pM, 4) inhibited in
vivo growth of established colon cancer xenografts in humanized NSG mice and 5) did not trigger production of
antibodies in mice. To further expand on this approach, the following Aims are proposed. Aim 1 will
characterize human and mouse reactive GlyTR bi-specific proteins targeting N-glycans. Aim 2 will
examine the efficacy and safety of GlyTR proteins targeting N-glycans using humanized NSG mice.
Aim 3 will examine the efficacy and safety of GlyTR proteins targeting N-glycans using mice with a
normal immune system. If successful, these experiments will provide proof of principal data for an entire new
class of cancer killing immunotherapeutic's capable of targeting multiple solid and hematopoietic cancers with
minimal toxicity.

## Key facts

- **NIH application ID:** 10229448
- **Project number:** 5U01CA233078-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Michael Demetriou
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $673,731
- **Award type:** 5
- **Project period:** 2018-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229448

## Citation

> US National Institutes of Health, RePORTER application 10229448, N-glycosylation and Immunotherapy for cancer (5U01CA233078-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10229448. Licensed CC0.

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