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Citations to this article

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation
Koji Haratani, … , Masaaki Miyazawa, Kazuhiko Nakagawa
Koji Haratani, … , Masaaki Miyazawa, Kazuhiko Nakagawa
Published October 29, 2019
Citation Information: J Clin Invest. 2020;130(1):374-388. https://doi.org/10.1172/JCI126598.
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Research Article Oncology Article has an altmetric score of 4

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

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Abstract

Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3–targeting (HER3–targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti–PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor–resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.

Authors

Koji Haratani, Kimio Yonesaka, Shiki Takamura, Osamu Maenishi, Ryoji Kato, Naoki Takegawa, Hisato Kawakami, Kaoru Tanaka, Hidetoshi Hayashi, Masayuki Takeda, Naoyuki Maeda, Takashi Kagari, Kenji Hirotani, Junji Tsurutani, Kazuto Nishio, Katsumi Doi, Masaaki Miyazawa, Kazuhiko Nakagawa

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 Total
Citations: 8 11 8 10 10 2 1 50
Citation information
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Citations to this article in year 2023 (8)

Title and authors Publication Year
Targeting HER3 for cancer treatment: a new horizon for an old target
Uliano J, Corvaja C, Curigliano G, Tarantino P
ESMO Open 2023
Antibody-drug conjugates: the clinical development in gastric cancer
Zhu Y, Zhou M, Kong W, Li C
Frontiers in Oncology 2023
Therapeutic index improvement of antibody-drug conjugates
Gerber HP, Gangwar S, Betts A
mAbs 2023
Disitamab vedotin in combination with immune checkpoint inhibitors for locally and locally advanced bladder urothelial carcinoma: a two-center’s real-world study
Wei Y, Zhang R, Yu C, Hong Z, Lin L, Li T, Chen J
Frontiers in pharmacology 2023
Uncovering therapeutic opportunities in the clinical development of antibody‐drug conjugates
Nieto\u2010Jiménez C, Sanvicente A, Díaz\u2010Tejeiro C, Moreno V, lopez de Sá A, Calvo E, Martínez\u2010López J, Pérez\u2010Segura P, Ocaña A
Clinical and Translational Medicine 2023
HER3: Toward the Prognostic Significance, Therapeutic Potential, Current Challenges, and Future Therapeutics in Different Types of Cancer
Majumder A
Cells 2023
The pathogenesis and potential therapeutic targets in sepsis
Zhang W, Jiang H, Wu G, Huang P, Wang H, An H, Liu S, Zhang W
2023
HER3-targeted therapeutic antibodies and antibody-drug conjugates in non-small cell lung cancer refractory to EGFR-tyrosine kinase inhibitors.
Larsen ME, Lyu H, Liu B
Chinese medical journal pulmonary and critical care medicine 2023

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ISSN: 0021-9738 (print), 1558-8238 (online)

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