# TCR Targeting Antibodies for the Treatment of T cell Cancers

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2022 · $216,810

## Abstract

Project Summary
 Antibody-mediated targeted immunotherapies are highly effective in killing cancer cells. T cell leukemias
and lymphomas, collectively known as T cell cancers, affect ~100,000 patients worldwide each year. Relapsed
T cell cancers respond poorly to aggressive chemotherapy with a 5-year survival between 7% to 38%. Thus, T
cell cancers particularly warrant antibody-mediated targeted immunotherapy to improve patient outcomes.
However, developing a T cell cancer targeting immunotherapy is challenging as the immunotherapy will have to
preserve enough healthy T cells to maintain a functioning immune system. T cells express the T cell receptor
(TCR) on the cell-surface. Although all T cells express TCR, they can be distinguished based on the TCR beta
chain constant region (TRBC) which is derived from one of two gene segments, TRBC1 or TRBC2. I led a team
that demonstrated that in healthy T cell populations, about 45% of cells express TRBC1 while the other 55%
express TRBC2. However, clonal T cell cancers express either TRBC1 or TRBC2 (Paul et al., Sci. Transl. Med.
2021). Thus, I hypothesize that antibody-mediated specific TRBC1 or TRBC2 targeting will eradicate the clonal
T cell cancers while preserving half of the healthy polyclonal T cell population. I also developed a TRBC1-
targeting bispecific antibody (αTRBC1) that selectively kills TRBC1+ T cell cancers (and TRBC1+ healthy T cells)
while preserving the healthy TRBC2+ T cells in vitro. These in vitro observations will require confirmation in
animal models before initiation of future human clinical trials. For Aim 1, I will determine the in vivo activity of the
αTRBC1 bispecific antibody. I will test the ability of αTRBC1 antibodies to induce tumor regression in multiple
mouse models of T cell cancers. I will then examine if the remaining healthy TRBC2+ T cells retain all of the
immune cell subsets required for a functioning immune system. I will also test if therapeutic pressure from the
αTRBC1 bispecific antibody will give rise to a low TCR expressing T cell population that will be resistant to
therapy. For Aim 2, I will test feasibility of TRBC2-targeting on T cell cancers. As a TRBC2-targeting antibody is
currently unavailable, I will use phage display to develop TRBC2-specific antibodies. I will then test the
cytotoxicity of TRBC2 targeting antibodies in vitro and in multiple mouse models of T cell cancers. Our TRBC-
directed antibodies will fill an unmet need for the treatment of T cell cancer patients. The proposed in vivo and
mechanistic studies will provide the pre-clinical validation required for the initiation of an early-phase human
clinical trials that will test the safety and efficacy of TRBC1- and TRBC2-targeting antibodies.
 My long-term goal is to become an independent laboratory-based physician-scientist focusing on
developing novel therapeutic approaches for T cell cancers. Through this proposal, I will also acquire the
research skills and career experience needed...

## Key facts

- **NIH application ID:** 10429145
- **Project number:** 1K08CA270403-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Suman Paul
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $216,810
- **Award type:** 1
- **Project period:** 2022-04-08 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10429145

## Citation

> US National Institutes of Health, RePORTER application 10429145, TCR Targeting Antibodies for the Treatment of T cell Cancers (1K08CA270403-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10429145. Licensed CC0.

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