# Translation development of a novel therapeutic antibody against drug-resistant B-cell malignancies

> **NIH NIH R21** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $225,765

## Abstract

Project Summary
Targeted immunotherapies such as monoclonal antibodies (mAbs) and CAR-T cells are highly successful
against hematological malignancies. However, these diseases remain incurable due to emerging resistance such
as to the anti-CD20 antibody, rituximab, or more recently CD19-CAR T cells. Thus, there is an urgent need to
develop new therapies that target B-cell malignancies. We can circumvent resistance by generating a novel
therapy against an alternative target. One target on B-cell tumors is B-cell activating factor receptor (BAFF-
R/TNFRSF13C), a tumor necrosis factor receptor superfamily member involved in B lymphocyte development
and survival. BAFF-R is expressed almost exclusively on B cells and its surface expression has been
documented on various human B-cell lymphomas. The BAFF/BAFF-R axis was previously targeted for
autoimmune diseases, however initial promise for tumor therapy has not yet been realized.
We began to develop chimeric antibodies targeting BAFF-R as a practical solution to quickly address the unmet
therapeutic need in drug-resistant B-cell lymphomas and leukemias. In our preliminary developments, our anti-
BAFF-R antibody has demonstrated efficacy in several in vitro and in vivo models. Our chimeric antibodies
demonstrated clear binding and potent antibody-dependent cell-mediated cytotoxicity (ADCC) against a range
of B-cell NHL and primary lymphomas from patients who progressed following exposure to rituximab. In vivo,
the anti-BAFF-R antibodies effectively eliminated tumors in drug-resistant lymphoma mouse models and
conferred significantly greater survival to antibody treated mice compared with controls.
The success thus far prompts our current hypothesis that BAFF-R is a suitable therapeutic antibody target for B-
cell lymphomas and leukemias. Our Specific Aim 1 proposes to investigate the therapeutic potential of BAFF-R
mAbs in relapsed B-cell malignancies resistant to CD19-target treatments. This aim will seek to develop and
investigate models of CD19-therapy resistant diseases. BAFF-R antibodies will be tested against CD19-knock
out tumor lines as well as primary patient samples from patients who relapsed with CD19-negative tumors.
Specific Aim 2 proposes to humanize BAFF-R mAbs and validate the lead candidate. This aim focuses on the
translatability and clinical relevance of our developed antibody. Humanizing the antibody will reduce negative
human-anti-mouse immune response to murine protein motifs on the anti-BAFF-R antibody. Furthermore,
validating the lead humanized antibody candidate in patient-derived xenograft (PDX) models will provide robust
evidence in support of its clinical translation and potential efficacy. Our novel antibody is developed to target a
B-cell tumor associated marker that has not been clinically targeted. Therefore, we seek to produce strong
evidence to present before the FDA in an Investigational New Drug (IND) application for a first-in-human clinical
trial of a novel therape...

## Key facts

- **NIH application ID:** 9833513
- **Project number:** 5R21CA223141-02
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** LARRY W KWAK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $225,765
- **Award type:** 5
- **Project period:** 2018-12-07 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9833513

## Citation

> US National Institutes of Health, RePORTER application 9833513, Translation development of a novel therapeutic antibody against drug-resistant B-cell malignancies (5R21CA223141-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9833513. Licensed CC0.

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