# Conditional control of universal antigen receptor signaling

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $442,414

## Abstract

PROJECT SUMMARY
Adoptive cell therapy using antigen receptor engineered T cells is a highly promising therapeutic approach, in
which cells are genetically modified to express an antigen receptor protein and are then adoptively transferred
into the patient. These cells then act as a “living drug” that can elicit potent therapeutic effects in response to
sensing a target antigen on a cell anywhere in the body. This approach is revolutionizing the treatment of blood
cancers and shows promise in cell therapies for treating solid tumors, auto-immune disease, and chronic viral
infection. We are developing highly modular universal adaptor versions of receptors, that we termed SNAP-CAR
and SNAP-synNotch. These receptors are “universal” as they can be chemically programmed to target any an-
tigen of interest by a co-administered adaptor molecule consisting of an antigen binding region conjugated to a
benzylguanine motif. Universal receptor systems can be used to target multiple antigens in a single patient or
across several disease indications by simply changing the antigen-targeting adaptor molecules.
Despite the tremendous promise of antigen receptor technologies, their implementation has been limited by
difficulties in attaining diseased cell-specificity through single antigen targeting, as well as unwanted on-tar-
get/off-disease toxicities and toxicities from overactive cells. We are addressing these technological gaps in
antigen receptor signaling-specificity by taking a chemical biology approach and combining chemical control of
biological systems through stimulus-reactive groups with receptor engineering.
The objective of this proposal is to develop universal antigen receptor systems that are conditionally activated
or deactivated by controller stimuli including small molecule exposure, as well as chemical changes characteristic
of diseased cellular microenvironments and antigen combinations. This will be achieved through completion of
the following aims: (1) Conditional control of universal antigen receptor signaling with OFF-switch adaptors. (2)
Conditional control of universal antigen receptor signaling using ON-switch adaptors. (3) Combinatorial control
of universal adaptor CAR T cells.
The underlying principle of our approach is a covalent bond formation between the adaptor and a self-labeling
SNAPtag enzyme fused to the receptor. Besides robust activation of cell signaling, the synthetic chemical linker
between the antibody and the receptor allows us to dial in a wide range of stimuli responses, including chemical
and biological triggers, based on distinct chemical designs of the linker molecules. Our characterization includes
demonstration in vitro using primary human T cells and in vivo in human cell xenograft mouse models.
Adoptive cell therapy with antigen receptor engineered cells is an active area of development and clinical use,
and the unprecedented level of conditional control enabled by the proposed systems will, as a long-term goa...

## Key facts

- **NIH application ID:** 10901896
- **Project number:** 5R01GM142007-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jason Jakob Lohmueller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,414
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901896

## Citation

> US National Institutes of Health, RePORTER application 10901896, Conditional control of universal antigen receptor signaling (5R01GM142007-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10901896. Licensed CC0.

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