• [Clinical Cancer Research] Anti–4-1BB×PDL1 Bispecific Antibody Reinvigorates Tumor-Specific Exhausted CD8+ T Cells and Enhances
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  • 2024-08-28 11:47:36|
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[Title]
Anti–4-1BB×PDL1 Bispecific Antibody Reinvigorates Tumor-Specific Exhausted CD8+ T Cells and Enhances the Efficacy of Anti-PD1 Blockade

[Author]

Seung Hyuck Jeon1,2, Gihoon You3, Junsik Park4, Youseung Chung1, Kyungjin Park3, Hyunjoo Kim3,Jaehyoung Jeon3, Youngkwang Kim3, Woo-Chan Son5, Da Som Jeong6, Eui-Cheol Shin1,Jung-Yun Lee4, Dai Hoon Han7, Jaeho Jung3, and Su-Hyung Park1

1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
2Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
3ABL Bio Inc., Seongnam, Republic of Korea.
4Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Republic of Korea.
5Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
6Department of Medical Science, AMIST, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
7Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
* S.H. Jeon, G. You, and J. Park contributed equally to this article.
* Corresponding Authors: Su-Hyung Park, Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 34141, Republic of Korea. E-mail: park3@kaist.ac.kr;
Jaeho Jung, ABL Bio Inc., 16 Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea. E-mail: jaeho.jung11@gmail.com;
and Dai Hoon Han, Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. E-mail: DHHAN@yuhs.ac


[Journal] 
 Clinical Cancer Research, 2024 May 14. doi: 10.1158/1078-0432.CCR-23-2864

[Abstract]

Purpose: To overcome the limited efficacy of immune checkpoint blockade, there is a need to find novel cancer immunotherapeutic strategies for the optimal treatment of cancer. The novel anti-4-1BB×PD-L1 bispecific antibody-ABL503 (also known as TJ-L14B)-was designed to simultaneously target PD-L1 and 4-1BB, and demonstrated strong antitumor T-cell responses without considerable toxicity. Here, we investigated how the combination of ABL503 and anti-PD-1 blockade affected the reinvigoration of exhausted tumor-infiltrating CD8+ T cells (CD8+ TILs) and anti-tumor efficacy.

Experimental design: Single cell suspensions of hepatocellular carcinoma and ovarian cancer from treatment-naive patients were used for immunophenotyping of CD8+ TILs and in vitro functional assays. Humanized hPD-1/hPD-L1/h4-1BB triple knock-in mice were used to evaluate the effects of ABL503 and anti-PD-1 blockade in vivo.

Results: We observed that ABL503 successfully restored the functions of 4-1BB+ exhausted CD8+ TILs, which were enriched for tumor-specific T cells but unresponsive to anti-PD-1 blockade. Importantly, compared to anti-PD-1 blockade alone, the combination of ABL503 and anti-PD-1 blockade further enhanced the functional restoration of human CD8+ TILs in vitro. Consistently, the combination of ABL503 with anti-PD-1 in vivo significantly alleviated tumor growth, and induced enhanced infiltration and activation of CD8+ TILs.

Conclusions: ABL503-a PD-L1 and 4-1BB dual-targeting bispecific antibody-elicits pronounced additive tumor growth inhibition, with increased infiltration and functionality of exhausted CD8+ T cells, which in turn enhances the anti-cancer effects of anti-PD-1 blockade. These promising findings suggest that ABL503 (TJ-L14B) in combination with PD-1 inhibitors will likely further enhance therapeutic benefit in clinical trials.

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