# Ultralong CDR3 antibodies targeting exhausted T cells

> **NIH NIH R21** · APPLIED BIOMEDICAL SCIENCE INSTITUTE · 2021 · $234,525

## Abstract

Abstract
T cell exhaustion prevents effective immune responses against many tumors and chronic infectious
diseases. Several antibody drugs termed “checkpoint inhibitors” target receptors (e.g. PD-1, PD-L1,
CTLA4) on exhausted T cells and can reverse their phenotype, leading to re-activation and the ability
to function as killer cells. While molecules such as PD-1, PD-L1, LAG-3, Tim-3, TIGIT and ICOS
have been described as markers of exhausted T cells, the cell surface phenotype is insufficiently
defined; thus, more markers and possible drug targets may exist on the surface of exhausted T cells.
Cluster of Differentiation (or “CD”) molecules were traditionally defined based on the reactivity of
monoclonal antibodies to the cell surface of leukocytes. These antibodies were identified by
immunizing rodents with preparations of white blood cells. It has recently become clear that the
antibody repertoires of different species are dramatically different with regards to their structural
diversity. Cows, in particular, have heavy chain complementarity determining regions (CDR H3s) of
up to 70 amino acids in length comprised of novel -ribbon “stalk” and disulfide bonded “knob” mini
domain structures. This contrasts with rodents, where antibodies for most CD molecules were
discovered, whose antibodies have flat binding surfaces comprised of very short (10 amino acids)
CDR H3 loops. Cow antibodies have the ability to bind epitopes that are relatively refractory to other
species’ repertoires, and provide a novel opportunity to further define the exhausted T cell surface.
To this end, we will immunize cattle with exhausted T cells and identify unique antibody:antigen pairs
and demonstrate functional activity of the antibodies by in vitro and in vivo reversal of the exhausted
T cell phenotype. Antibodies from this research could serve as experimental therapeutics for cancer
or chronic infection, diagnostics, or important research tools to further define exhausted T cell subsets
and differentiation pathways.

## Key facts

- **NIH application ID:** 10104438
- **Project number:** 5R21AI144828-02
- **Recipient organization:** APPLIED BIOMEDICAL SCIENCE INSTITUTE
- **Principal Investigator:** Vaughn Vasil Smider
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,525
- **Award type:** 5
- **Project period:** 2020-02-11 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104438

## Citation

> US National Institutes of Health, RePORTER application 10104438, Ultralong CDR3 antibodies targeting exhausted T cells (5R21AI144828-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10104438. Licensed CC0.

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