한빛사 논문
Gihoon You1,*, Yangsoon Lee2,*, Yeon-Woo Kang1, Han Wook Park1, Kyeongsu Park2, Hyekang Kim1, Young-Min Kim1, Sora Kim1, Ji-Hae Kim3, Dain Moon1, Hyejin Chung2, Wonjun Son2, Ui-jung Jung2, Eunyoung Park2, Shinai Lee2, Yong-Gyu Son2, Jaehyun Eom2, Jonghwa Won2, Yunji Park1, Jaeho Jung2,† and Seung-Woo Lee1,3,†
1Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
2ABL Bio Inc., Seongnam, Republic of Korea.
3Department of Life Sciences, POSTECH, Pohang, Republic of Korea.
†Corresponding author.
*These authors contributed equally to this work.
Abstract
Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB–dependent antitumor response in hB7-H3–overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1+Tim-3+ “terminally differentiated” subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB–expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3–positive cancers as monotherapy and combination therapy with PD-1 blockade.
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