# Structural Surfaceomics: A Strategy for Immunotherapy Target Discovery

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $203,236

## Abstract

PROJECT SUMMARY/ABSTRACT
Engineered cellular therapies, such as CAR-T cells, hold great promise as “living drugs”. However,
the application of this approach beyond B-cell origin malignancies has been hampered by a lack of
tumor-specific cell surface antigen targets. Current methods to identify new targets rely largely on
expression patterns from RNA-seq data. However, the limitations of this transcriptome-based strategy
have rapidly become apparent. We were struck by the recent serendipitous discovery of a tumor-
specific surface antigen in the blood cancer multiple myeloma, amenable to CAR-T targeting, defined
not by its expression but by its structural conformation compared to normal hematopoietic cells. The
central hypothesis of this proposal is that many additional conformation-specific tumor antigens likely
exist, across cancers, but currently there is no technology yet available to detect them. Here we aim
to develop such a technology, combining our expertise in cell surface proteomics with crosslinking
mass spectrometry, which we call “structural surfaceomics”. While this approach could be applied to
any cancer, here we first explore acute myeloid leukemia (AML), a hematologic malignancy with poor
clinical outcomes and a lack of highly-specific cell surface targets. In preliminary data, utilizing an
initial version of the structural surfaceomics technology, we have already identified a novel
conformation-specific antigen in AML that may be a promising therapeutic target. Here, we propose
two Specific Aims: 1) Further development of the structural surfaceomics approach. Our preliminary
protocol is restricted to highly-expressed surface antigens with sufficient lysine crosslinks to report on
structural changes. To broaden applicability, we first aim to implement recently-described XL-MS
strategies that can achieve much higher proteomic coverage. We will further assess the performance
of our method using biochemical control of specific surface antigens, as well as profile additional AML
lines for novel target discovery. 2) Development of novel CAR-T's targeting a conformation-specific
AML antigen. We will generate CAR-T compatible binders both using a standard scFv approach,
based on an existing murine antibody, as well as fully in vitro-selected nanobodies via yeast display.
Our lab has recently demonstrated the latter strategy as a promising approach for cellular therapy in
acute leukemia (Nix et al., in revision for Cancer Discovery). We will perform initial in vitro and in vivo
validation of these cellular therapies. Overall, we anticipate developing an approach to identify an
entirely new class of immunotherapy targets. Furthermore, we aim to demonstrate that our approach
can nominate a promising cellular therapeutic candidate specific for AML. In future work, beyond this
pilot funding, we anticipate applying structural surfaceomics to broader profiling of malignancies, as
well as more complete preclinical validation of our AML conformat...

## Key facts

- **NIH application ID:** 10290239
- **Project number:** 1R21CA263229-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Arun P. Wiita
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $203,236
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10290239

## Citation

> US National Institutes of Health, RePORTER application 10290239, Structural Surfaceomics: A Strategy for Immunotherapy Target Discovery (1R21CA263229-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10290239. Licensed CC0.

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