# Eliminating B Cell Precursor Acute Lymphoblastic Leukemia by Targeting the Uniquely Specific Pre-B Cell Receptor

> **NIH NIH R21** · PASCAL BIOSCIENCES US, INC. · 2022 · $254,143

## Abstract

ABSTRACT
B cell precursor acute lymphoblastic leukemia (BCP-ALL), a malignancy that arises from mutant pre-B cells, is
the most common childhood leukemia but also occurs in adults. While effective in up to 90% of patients, current
chemo- and targeted therapies for BCP-ALL temporarily destroy the humoral (antibody-producing) arm of the
immune system and cause toxicities with long term consequences. The goal of this R21 grant proposal is to
engage in conceptual research regarding the utility of the pre-B cell receptor (pre-BCR) as a unique therapeutic
target for the treatment of BCP-ALL. The pre-BCR comprises an immunoglobulin (Ig) heavy chain and a
surrogate light chain (SLC) together with the signaling molecules Ig alpha and Ig beta. The SLC is composed of
two noncovalently-linked polypeptides, VpreB and l5. In normal tissues, the pre-BCR is expressed only in pre-
B cells but not in more mature B cells nor in any other tissues. Importantly, our preliminary data suggest that
VpreB and l5 are expressed in >90% of BCP-ALL. We therefore generated high avidity monoclonal antibodies
(mAbs) specific for VpreB and l5 and found that the mAbs are internalized into BCP-ALL cells expressing the
pre-BCR. Internalization is an important prerequisite for the antibody component of an antibody-drug conjugate
(ADC). Our central hypothesis is that attacking BCP-ALL with an ADC specific for VpreB or l5 will eliminate the
leukemia cells while sparing the mature humoral immune system to combat infection. Our goal is to obtain proof-
of-concept data that first, confirms internalization of VpreB mAbs in several BCP-ALL cell lines and allows
selection of a single, most efficiently internalizing lead mAb (Specific Aim 1); second, show at the protein level
the widespread expression of the pre-BCR in 35 BCP-ALL patient leukemia samples (Specific Aim 2); and third,
demonstrate the ability of our lead VpreB ADC to kill established and patient-derived BCP-ALL cell lines in vitro,
ex vivo, and in a patient-derived xenograft model (Specific Aim 3). We hope that this research will support the
development of a new BCP-ALL therapeutic that will safely eliminate leukemia cells while sparing the humoral
immune system and ultimately supplanting chemotherapy so that patients can achieve full remission without
short- or long-term adverse consequences.

## Key facts

- **NIH application ID:** 10374764
- **Project number:** 5R21CA256319-02
- **Recipient organization:** PASCAL BIOSCIENCES US, INC.
- **Principal Investigator:** Larry W. Tjoelker
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $254,143
- **Award type:** 5
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374764

## Citation

> US National Institutes of Health, RePORTER application 10374764, Eliminating B Cell Precursor Acute Lymphoblastic Leukemia by Targeting the Uniquely Specific Pre-B Cell Receptor (5R21CA256319-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10374764. Licensed CC0.

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