Evidence supporting a role for the immune checkpoint protein B7-H3 in NK cell-mediated cytotoxicity against AML

Anudishi Tyagi; Stanley Ly; Fouad El-Dana; Bin Yuan; Appalaraju Jaggupilli; Sabrina Grimm; Marina Konopleva; Hans Jörg Bühring; V. Lokesh Battula

doi:10.1182/blood.2021014671

Evidence supporting a role for the immune checkpoint protein B7-H3 in NK cell-mediated cytotoxicity against AML

Anudishi Tyagi, Stanley Ly, Fouad El-Dana, Bin Yuan, Appalaraju Jaggupilli, Sabrina Grimm, Marina Konopleva, Hans Jörg Bühring, V. Lokesh Battula

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3⁺ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop region of B7-H3, which is known to regulate the immunosuppressive function of B7-H3. Furthermore, treatment with ChT-1A5 in combination with human NK cells significantly prolonged survival in AML patient-derived xenograft (PDX) models. Our results suggest that the ChT-1A5 antibody can inhibit the immunosuppressive function of B7-H3 protein as well as induce ADCC in B7-H3⁺ AML.

Original language	English (US)
Pages (from-to)	2782-2796
Number of pages	15
Journal	Blood
Volume	139
Issue number	18
DOIs	https://doi.org/10.1182/blood.2021014671
State	Published - May 5 2022

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood.2021014671

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title = "Evidence supporting a role for the immune checkpoint protein B7-H3 in NK cell-mediated cytotoxicity against AML",

abstract = "We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop region of B7-H3, which is known to regulate the immunosuppressive function of B7-H3. Furthermore, treatment with ChT-1A5 in combination with human NK cells significantly prolonged survival in AML patient-derived xenograft (PDX) models. Our results suggest that the ChT-1A5 antibody can inhibit the immunosuppressive function of B7-H3 protein as well as induce ADCC in B7-H3+ AML.",

author = "Anudishi Tyagi and Stanley Ly and Fouad El-Dana and Bin Yuan and Appalaraju Jaggupilli and Sabrina Grimm and Marina Konopleva and B{\"u}hring, {Hans J{\"o}rg} and Battula, {V. Lokesh}",

note = "Funding Information: The authors thank the Anderson Monoclonal Antibody Facility, supported in part by CCSG grant number P30 CA016672 from the National Institutes of Health/National Cancer Institute. The authors also thank Numsen Hail as well as Amy L. Ninetto, Sarah Bronson, and Bryan Tutt of the Research Medical Library at Anderson for editing the manuscript. Funding Information: This work was supported by funding from the Leukemia and Lymphoma Society, the Emerson Collective, and bridge funding from MD Anderson Cancer Center. Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",

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month = may,

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doi = "10.1182/blood.2021014671",

language = "English (US)",

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T1 - Evidence supporting a role for the immune checkpoint protein B7-H3 in NK cell-mediated cytotoxicity against AML

AU - Tyagi, Anudishi

AU - Ly, Stanley

AU - El-Dana, Fouad

AU - Yuan, Bin

AU - Jaggupilli, Appalaraju

AU - Grimm, Sabrina

AU - Konopleva, Marina

AU - Bühring, Hans Jörg

AU - Battula, V. Lokesh

N1 - Funding Information: The authors thank the Anderson Monoclonal Antibody Facility, supported in part by CCSG grant number P30 CA016672 from the National Institutes of Health/National Cancer Institute. The authors also thank Numsen Hail as well as Amy L. Ninetto, Sarah Bronson, and Bryan Tutt of the Research Medical Library at Anderson for editing the manuscript. Funding Information: This work was supported by funding from the Leukemia and Lymphoma Society, the Emerson Collective, and bridge funding from MD Anderson Cancer Center. Publisher Copyright: © 2022 American Society of Hematology

PY - 2022/5/5

Y1 - 2022/5/5

N2 - We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop region of B7-H3, which is known to regulate the immunosuppressive function of B7-H3. Furthermore, treatment with ChT-1A5 in combination with human NK cells significantly prolonged survival in AML patient-derived xenograft (PDX) models. Our results suggest that the ChT-1A5 antibody can inhibit the immunosuppressive function of B7-H3 protein as well as induce ADCC in B7-H3+ AML.

AB - We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop region of B7-H3, which is known to regulate the immunosuppressive function of B7-H3. Furthermore, treatment with ChT-1A5 in combination with human NK cells significantly prolonged survival in AML patient-derived xenograft (PDX) models. Our results suggest that the ChT-1A5 antibody can inhibit the immunosuppressive function of B7-H3 protein as well as induce ADCC in B7-H3+ AML.

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Evidence supporting a role for the immune checkpoint protein B7-H3 in NK cell-mediated cytotoxicity against AML

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