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B7-H3×4-1BB 双特异性抗体通过增强终末分化的 CD8 肿瘤浸润淋巴细胞增强抗肿瘤免疫。

B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8 tumor-infiltrating lymphocytes.

机构信息

Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.

ABL Bio Inc., Seongnam, Republic of Korea.

出版信息

Sci Adv. 2021 Jan 15;7(3). doi: 10.1126/sciadv.aax3160. Print 2021 Jan.

DOI:10.1126/sciadv.aax3160
PMID:33523913
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7810375/
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-1Tim-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.

摘要

4-1BB 激动剂的癌症免疫疗法由于剂量限制毒性而进一步限制了其临床发展。在这里，我们开发了一种针对人 B7-H3（hB7-H3）和小鼠或人 4-1BB 的双特异性抗体（bsAb；B7-H3×4-1BB），以限制肿瘤中的 4-1BB 刺激。B7-H3×m4-1BB 在 hB7-H3 过表达的肿瘤模型中引发了依赖于 4-1BB 的抗肿瘤反应，而没有全身毒性。bsAb 主要靶向肿瘤中的 CD8 T 细胞，并增加其增殖和细胞因子产生。在肿瘤中的 CD8 T 细胞群体中，4-1BB 仅在 PD-1Tim-3“终末分化”亚群上表达，而 bsAb 增强这些细胞消除肿瘤的能力。此外，bsAb 和 PD-1 阻断的联合抑制肿瘤生长，同时进一步增加终末分化的 CD8 T 细胞。B7-H3×h4-1BB 在表达 h4-1BB 的小鼠中也显示出抗肿瘤活性。我们的数据表明，B7-H3×4-1BB 是一种针对 B7-H3 阳性癌症的有效且安全的治疗剂，可作为单药治疗以及与 PD-1 阻断的联合治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/4890f043c12d/aax3160-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/f2239ca348da/aax3160-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/d5f7d597524b/aax3160-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/bf3c5bb8cd76/aax3160-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/e571e8305df1/aax3160-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/07e22a418f89/aax3160-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/4890f043c12d/aax3160-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/f2239ca348da/aax3160-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/d5f7d597524b/aax3160-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/bf3c5bb8cd76/aax3160-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/e571e8305df1/aax3160-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/07e22a418f89/aax3160-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a866/7810375/4890f043c12d/aax3160-F6.jpg

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2
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3
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iScience. 2025 Jun 4;28(7):112829. doi: 10.1016/j.isci.2025.112829. eCollection 2025 Jul 18.
4
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5
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Nat Rev Urol. 2025 Apr 1. doi: 10.1038/s41585-025-01014-w.
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