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Cancer Immunotherapy Targeting Tn Antigen

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA261408-01A1
Agency Tracking Number: R41CA261408
Amount: $398,178.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 100
Solicitation Number: PA20-265
Timeline
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-08-01
Award End Date (Contract End Date): 2022-07-31
Small Business Information
5151 CALIFORNIA AVE, #150
Irvine, CA 92617-3206
United States
DUNS: 080209701
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 MICHAEL DEMETRIOU
 (949) 824-9775
 mdemetri@uci.edu
Business Contact
 RAYMOND ZHOU
Phone: (916) 612-9988
Email: raymondzhou@glytrtherapeutics.com
Research Institution
 UNIVERSITY OF CALIFORNIA-IRVINE
 
160 ALDRICH HALL
IRVINE, CA 92697-0001
United States

 Nonprofit College or University
Abstract

AbstractCancer immunotherapeutic bi-specific proteins and engineered Chimeric Antigen Receptor T cells (CAR
T) have shown remarkable clinical activity, with complete response rates as high as ~90% for B cell malignancies.
However, applying these two therapeutic approaches to the vast majority of cancer types is restricted
by multiple factors. First, there are only a 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. Second,
as each individual bi-specific protein and/or CAR T cell only target a single cancer type, different bi-specific
and/or CAR T cells will need to be developed for each cancer type. This greatly increases development time and
costs. Third, neither therapy is able to effectively target the most abundant and widely expressed cell surface
cancer antigens known, namely Tumor associated carbohydrate antigens (TACA’s). Many cancer specific
antigens are not proteins, but rather complex carbohydrates that have limited or no expression in normal tissues.
Indeed, altered glycosylation is a near universal feature of cancer. While TACA’s have been known for decades,
generation of effective 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 the Tn antigen, an abnormal
O-linked carbohydrate common on many solid and hematopoietic cancers but not present on normal
tissue. We have termed this technology as Glycan-dependent T cell Recruiter (GlyTR, pronounced
‘glitter’). We have generated and optimized a GlyTR bi-specific protein that 1) specifically binds to both Tn
antigen and CD3, 2) activated T cells in the presence but not absence of Tn+ cancer cells and 3) induced T cell
dependent killing of diverse solid and liquid cancer cells in vitro and in vivo. However, serum half-life was ~2 hrs,
which is similar to the FDA approved bi-specific protein Blincyto that requires continuous intravenous infusion
(via a pump) over 28-days (first 9 days in hospital). To avoid this cumbersome treatment regimen for GlyTR,
here we propose to extend the half-life by adding a human-serum albumin (HSA) domain. The half-life of HSA
is ~3 weeks and has been successfully fused to therapeutic proteins to markedly increase half-life, including two
FDA approved therapeutics. Here we propose to genetically fuse HSA to GlyTR (HSA-GlyTR) and confirm
binding to Tn antigen, cancer-killing activity and improved half-life. Specifically, we propose the following two
Aims. Aim 1 optimizes the HSA-GlyTR bi-specific protein for activity and drug development. Aim 2 explores the
efficacy and safety of the optimized HSA-GlyTR bi-specific protein. If successful, these experiments will allow
subsequent IND enabling studies to develop an entire new class of cancer killing immunotherapeutic’s uniquely
capable of targeting multiple solid and hematopoietic cancers with a single therapeutic.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 examine the possibility of a novel
technology that directs immune cells to kill cancer cells based on expression of altered
carbohydrates.

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

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