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

Award Number: R21CA223141
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/07/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2021

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Translation development of a novel therapeutic antibody against drug-resistant B-cell malignancies - 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 therapeutic to treat drug-resistant B-cell malignancies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	2	3/9/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $225,765 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	2	1/13/2020	NON-COMPETING CONTINUATION	$22,577
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	002	2	7/2/2020	NON-COMPETING CONTINUATION	$0
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	2	11/15/2019	NON-COMPETING CONTINUATION	$203,188
														Subtotal = $225,765

Issue Date FY: 2019 ( Subtotal = $188,138 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	1	12/7/2018	NEW	$188,138
														Subtotal = $188,138

Grand Total All Awards = $413,903

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

Award Number: R21CA223141

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/07/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2021

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