LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation

Eunsil Sung; Minkyung Ko; Ju young Won; Yunju Jo; Eunyoung Park; Hyunjoo Kim; Eunji Choi; Ui jung Jung; Jaehyoung Jeon; Youngkwang Kim; Hyejin Ahn; Da som Choi; Seunghyun Choi; Youngeun Hong; Hyeyoung Park; Hanbyul Lee; Yong Gyu Son; Kyeongsu Park; Jonghwa Won; Soo Jin Oh; Seonmin Lee; Kyu pyo Kim; Changhoon Yoo; Hyun Kyu Song; Hyung seung Jin; Jaeho Jung; Yoon Park

doi:10.1016/j.ymthe.2022.05.003

LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation

Eunsil Sung, Minkyung Ko, Ju young Won, Yunju Jo, Eunyoung Park, Hyunjoo Kim, Eunji Choi, Ui jung Jung, Jaehyoung Jeon, Youngkwang Kim, Hyejin Ahn, Da som Choi, Seunghyun Choi, Youngeun Hong, Hyeyoung Park, Hanbyul Lee, Yong Gyu Son, Kyeongsu Park, Jonghwa Won, Soo Jin OhSeonmin Lee, Kyu pyo Kim, Changhoon Yoo, Hyun Kyu Song, Hyung seung Jin, Jaeho Jung, Yoon Park

Department of Life Sciences

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

38 Citations (Scopus)

Abstract

Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4⁺ and CD8⁺ T cells with a higher degree than a combination of single anti-LAG-3 and anti-PD-L1. The augmented effector T cell responses by ABL501 resulted in mitigating regulatory-T-cell-mediated immunosuppression. Mechanistically, the simultaneous binding of ABL501 to LAG-3 and PD-L1 promotes dendritic cell (DC) activation and tumor cell conjugation with T cells that subsequently mounts effective CD8⁺ T cell responses. ABL501 demonstrates its potent in vivo antitumor efficacy in a humanized xenograft model and with knockin mice expressing human orthologs. The immune profiling analysis of peripheral blood reveals an increased abundance of LAG-3^hiPD-1^hi memory CD4⁺ T cell subset in relapsed cholangiocarcinoma patients after gemcitabine plus cisplatin therapy, which are more responsive to ABL501. This study supports the clinical evaluation of ABL501 as a novel cancer immunotherapeutic, and a first-in-human trial has started (NCT05101109).

Original language	English
Pages (from-to)	2800-2816
Number of pages	17
Journal	Molecular Therapy
Volume	30
Issue number	8
DOIs	https://doi.org/10.1016/j.ymthe.2022.05.003
Publication status	Published - 2022 Aug 3

Bibliographical note

Funding Information:
We thank the core facilities of Genetically Engineered Animal Core and flow cytometry at the Convergence Medicine Research Center (CREDIT), Asan Medical Center. This work was supported by an intramural grant of KIST, by the National Research Foundation of Korea grants (NRF-2021R1A2C1003551 to H.J. NRF-2020M3A9G7103935 to H.J. and NRF-2021R1A2C2006647 to Y.P.), and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare of South Korea (HI20C0117 to J. Jung). Conception and design, E.S. E.P. Jonghwa Won, H.J. J. Jung, and Y.P.; development of methodology, E.S. M.K. H.J. J. Jung, and Y.P.; acquisition of data, Ju-young Won, Y.J. E.C. U.J. J. Jeon, Y.K. H.A. D.C. S.C. Y.H. H.P. H.L. Y.-G.S. and K.P.; technical and material support, S.J.O. S.L. K.K. C.Y. and H.K.S.; analysis and interpretation of data, E.S. E.P. H.K. H.P. H.L. Jonghwa Won, H.J. J. Jung, and Y.P.; writing the manuscript, E.S. H.J. J. Jung, and Y.P.; study supervision, H.J. J. Jung, and Y.P. E.S. E.P. H.K. U.J. J. Jeon, Y.K. Y.H. H.P. H.L. Y.-G.S. K.P. Jonghwa Won, and J. Jung are employees of ABL Bio Inc. The other authors declare no competing interests.

Funding Information:
We thank the core facilities of Genetically Engineered Animal Core and flow cytometry at the Convergence Medicine Research Center (CREDIT), Asan Medical Center. This work was supported by an intramural grant of KIST , by the National Research Foundation of Korea grants ( NRF-2021R1A2C1003551 to H.J., NRF-2020M3A9G7103935 to H.J., and NRF-2021R1A2C2006647 to Y.P.), and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute , funded by the Ministry of Health & Welfare of South Korea ( HI20C0117 to J. Jung).

Publisher Copyright:
© 2022 The Author(s)

Keywords

LAG-3
PD-L1
bispecific antibody
cancer immunotherapy
cholangiocarcinoma
immune checkpoint inhibitor

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ymthe.2022.05.003

Cite this

Sung, E., Ko, M., Won, J. Y., Jo, Y., Park, E., Kim, H., Choi, E., Jung, U. J., Jeon, J., Kim, Y., Ahn, H., Choi, D. S., Choi, S., Hong, Y., Park, H., Lee, H., Son, Y. G., Park, K., Won, J., ... Park, Y. (2022). LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation. Molecular Therapy, 30(8), 2800-2816. https://doi.org/10.1016/j.ymthe.2022.05.003

Sung, E, Ko, M, Won, JY, Jo, Y, Park, E, Kim, H, Choi, E, Jung, UJ, Jeon, J, Kim, Y, Ahn, H, Choi, DS, Choi, S, Hong, Y, Park, H, Lee, H, Son, YG, Park, K, Won, J, Oh, SJ, Lee, S, Kim, KP, Yoo, C, Song, HK, Jin, HS, Jung, J & Park, Y 2022, 'LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation', Molecular Therapy, vol. 30, no. 8, pp. 2800-2816. https://doi.org/10.1016/j.ymthe.2022.05.003

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title = "LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation",

abstract = "Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4+ and CD8+ T cells with a higher degree than a combination of single anti-LAG-3 and anti-PD-L1. The augmented effector T cell responses by ABL501 resulted in mitigating regulatory-T-cell-mediated immunosuppression. Mechanistically, the simultaneous binding of ABL501 to LAG-3 and PD-L1 promotes dendritic cell (DC) activation and tumor cell conjugation with T cells that subsequently mounts effective CD8+ T cell responses. ABL501 demonstrates its potent in vivo antitumor efficacy in a humanized xenograft model and with knockin mice expressing human orthologs. The immune profiling analysis of peripheral blood reveals an increased abundance of LAG-3hiPD-1hi memory CD4+ T cell subset in relapsed cholangiocarcinoma patients after gemcitabine plus cisplatin therapy, which are more responsive to ABL501. This study supports the clinical evaluation of ABL501 as a novel cancer immunotherapeutic, and a first-in-human trial has started (NCT05101109).",

keywords = "LAG-3, PD-L1, bispecific antibody, cancer immunotherapy, cholangiocarcinoma, immune checkpoint inhibitor",

author = "Eunsil Sung and Minkyung Ko and Won, {Ju young} and Yunju Jo and Eunyoung Park and Hyunjoo Kim and Eunji Choi and Jung, {Ui jung} and Jaehyoung Jeon and Youngkwang Kim and Hyejin Ahn and Choi, {Da som} and Seunghyun Choi and Youngeun Hong and Hyeyoung Park and Hanbyul Lee and Son, {Yong Gyu} and Kyeongsu Park and Jonghwa Won and Oh, {Soo Jin} and Seonmin Lee and Kim, {Kyu pyo} and Changhoon Yoo and Song, {Hyun Kyu} and Jin, {Hyung seung} and Jaeho Jung and Yoon Park",

note = "Funding Information: We thank the core facilities of Genetically Engineered Animal Core and flow cytometry at the Convergence Medicine Research Center (CREDIT), Asan Medical Center. This work was supported by an intramural grant of KIST, by the National Research Foundation of Korea grants (NRF-2021R1A2C1003551 to H.J. NRF-2020M3A9G7103935 to H.J. and NRF-2021R1A2C2006647 to Y.P.), and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare of South Korea (HI20C0117 to J. Jung). Conception and design, E.S. E.P. Jonghwa Won, H.J. J. Jung, and Y.P.; development of methodology, E.S. M.K. H.J. J. Jung, and Y.P.; acquisition of data, Ju-young Won, Y.J. E.C. U.J. J. Jeon, Y.K. H.A. D.C. S.C. Y.H. H.P. H.L. Y.-G.S. and K.P.; technical and material support, S.J.O. S.L. K.K. C.Y. and H.K.S.; analysis and interpretation of data, E.S. E.P. H.K. H.P. H.L. Jonghwa Won, H.J. J. Jung, and Y.P.; writing the manuscript, E.S. H.J. J. Jung, and Y.P.; study supervision, H.J. J. Jung, and Y.P. E.S. E.P. H.K. U.J. J. Jeon, Y.K. Y.H. H.P. H.L. Y.-G.S. K.P. Jonghwa Won, and J. Jung are employees of ABL Bio Inc. The other authors declare no competing interests. Funding Information: We thank the core facilities of Genetically Engineered Animal Core and flow cytometry at the Convergence Medicine Research Center (CREDIT), Asan Medical Center. This work was supported by an intramural grant of KIST , by the National Research Foundation of Korea grants ( NRF-2021R1A2C1003551 to H.J., NRF-2020M3A9G7103935 to H.J., and NRF-2021R1A2C2006647 to Y.P.), and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute , funded by the Ministry of Health & Welfare of South Korea ( HI20C0117 to J. Jung). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = aug,

day = "3",

doi = "10.1016/j.ymthe.2022.05.003",

language = "English",

volume = "30",

pages = "2800--2816",

journal = "Molecular Therapy",

issn = "1525-0016",

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number = "8",

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TY - JOUR

T1 - LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation

AU - Sung, Eunsil

AU - Ko, Minkyung

AU - Won, Ju young

AU - Jo, Yunju

AU - Park, Eunyoung

AU - Kim, Hyunjoo

AU - Choi, Eunji

AU - Jung, Ui jung

AU - Jeon, Jaehyoung

AU - Kim, Youngkwang

AU - Ahn, Hyejin

AU - Choi, Da som

AU - Choi, Seunghyun

AU - Hong, Youngeun

AU - Park, Hyeyoung

AU - Lee, Hanbyul

AU - Son, Yong Gyu

AU - Park, Kyeongsu

AU - Won, Jonghwa

AU - Oh, Soo Jin

AU - Lee, Seonmin

AU - Kim, Kyu pyo

AU - Yoo, Changhoon

AU - Song, Hyun Kyu

AU - Jin, Hyung seung

AU - Jung, Jaeho

AU - Park, Yoon

N1 - Funding Information: We thank the core facilities of Genetically Engineered Animal Core and flow cytometry at the Convergence Medicine Research Center (CREDIT), Asan Medical Center. This work was supported by an intramural grant of KIST, by the National Research Foundation of Korea grants (NRF-2021R1A2C1003551 to H.J. NRF-2020M3A9G7103935 to H.J. and NRF-2021R1A2C2006647 to Y.P.), and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare of South Korea (HI20C0117 to J. Jung). Conception and design, E.S. E.P. Jonghwa Won, H.J. J. Jung, and Y.P.; development of methodology, E.S. M.K. H.J. J. Jung, and Y.P.; acquisition of data, Ju-young Won, Y.J. E.C. U.J. J. Jeon, Y.K. H.A. D.C. S.C. Y.H. H.P. H.L. Y.-G.S. and K.P.; technical and material support, S.J.O. S.L. K.K. C.Y. and H.K.S.; analysis and interpretation of data, E.S. E.P. H.K. H.P. H.L. Jonghwa Won, H.J. J. Jung, and Y.P.; writing the manuscript, E.S. H.J. J. Jung, and Y.P.; study supervision, H.J. J. Jung, and Y.P. E.S. E.P. H.K. U.J. J. Jeon, Y.K. Y.H. H.P. H.L. Y.-G.S. K.P. Jonghwa Won, and J. Jung are employees of ABL Bio Inc. The other authors declare no competing interests. Funding Information: We thank the core facilities of Genetically Engineered Animal Core and flow cytometry at the Convergence Medicine Research Center (CREDIT), Asan Medical Center. This work was supported by an intramural grant of KIST , by the National Research Foundation of Korea grants ( NRF-2021R1A2C1003551 to H.J., NRF-2020M3A9G7103935 to H.J., and NRF-2021R1A2C2006647 to Y.P.), and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute , funded by the Ministry of Health & Welfare of South Korea ( HI20C0117 to J. Jung). Publisher Copyright: © 2022 The Author(s)

PY - 2022/8/3

Y1 - 2022/8/3

N2 - Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4+ and CD8+ T cells with a higher degree than a combination of single anti-LAG-3 and anti-PD-L1. The augmented effector T cell responses by ABL501 resulted in mitigating regulatory-T-cell-mediated immunosuppression. Mechanistically, the simultaneous binding of ABL501 to LAG-3 and PD-L1 promotes dendritic cell (DC) activation and tumor cell conjugation with T cells that subsequently mounts effective CD8+ T cell responses. ABL501 demonstrates its potent in vivo antitumor efficacy in a humanized xenograft model and with knockin mice expressing human orthologs. The immune profiling analysis of peripheral blood reveals an increased abundance of LAG-3hiPD-1hi memory CD4+ T cell subset in relapsed cholangiocarcinoma patients after gemcitabine plus cisplatin therapy, which are more responsive to ABL501. This study supports the clinical evaluation of ABL501 as a novel cancer immunotherapeutic, and a first-in-human trial has started (NCT05101109).

AB - Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4+ and CD8+ T cells with a higher degree than a combination of single anti-LAG-3 and anti-PD-L1. The augmented effector T cell responses by ABL501 resulted in mitigating regulatory-T-cell-mediated immunosuppression. Mechanistically, the simultaneous binding of ABL501 to LAG-3 and PD-L1 promotes dendritic cell (DC) activation and tumor cell conjugation with T cells that subsequently mounts effective CD8+ T cell responses. ABL501 demonstrates its potent in vivo antitumor efficacy in a humanized xenograft model and with knockin mice expressing human orthologs. The immune profiling analysis of peripheral blood reveals an increased abundance of LAG-3hiPD-1hi memory CD4+ T cell subset in relapsed cholangiocarcinoma patients after gemcitabine plus cisplatin therapy, which are more responsive to ABL501. This study supports the clinical evaluation of ABL501 as a novel cancer immunotherapeutic, and a first-in-human trial has started (NCT05101109).

KW - LAG-3

KW - PD-L1

KW - bispecific antibody

KW - cancer immunotherapy

KW - cholangiocarcinoma

KW - immune checkpoint inhibitor

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DO - 10.1016/j.ymthe.2022.05.003

M3 - Article

C2 - 35526096

AN - SCOPUS:85130369551

SN - 1525-0016

VL - 30

SP - 2800

EP - 2816

JO - Molecular Therapy

JF - Molecular Therapy

IS - 8

ER -

LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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