Article Text

Download PDFPDF

845 ABL503 (TJ-L14B), PD-L1×4–1BB bispecific antibody, reinvigorates exhausted tumor-infiltrating CD8+ T cells and synergizes with PD-1 blockade
  1. Gihoon You1,
  2. Seung Hyuck Jeon2,
  3. Kyungjin Park1,
  4. Hyunjoo Kim1,
  5. Jaehyoung Jeon1,
  6. Youngkwang Kim1,
  7. Claire Xu3,
  8. Xuejun Liu4,
  9. Su-Hyung Park2 and
  10. Jaeho Jung1
  1. 1ABL Bio, Inc., Seongnam-si, Republic of Korea
  2. 2Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
  3. 3I-Mab Biopharma, Co., Ltd., Lawrenceville Township, NJ, USA
  4. 4I-Mab Biopharma, Co., Ltd., San Diego, CA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background ABL503 (also known as TJ-L14B) is a bispecific antibody designed to simultaneously target PD-L1 and 4–1BB, and functions as both ‘PD-(L)1 inhibitor’ and ‘PD-L1-dependent 4–1BB agonist’, overcoming the known 4–1BB agonist-related hepatotoxicity in clinical studies. Previously, we showed that ABL503 (TJ-L14B) was able to activate 4–1BB signaling in PD-L1 engagement-dependent manner and successfully exerted its function without considerable toxicities. The phase I clinical trial is currently ongoing in the U.S., in patients with locally advanced/metastatic solid tumors (NCT04762641). Published data on PD-L1×4–1BB bispecific antibodies suggest therapeutic synergy could be provided by the combination of anti-PD-1 and ABL503 (TJ-L14B) to broader patient populations, so we performed combination studies with additional PD-1-blocking immunotherapy. Given that the tumor-infiltrating CD8+ T cells reportedly play a pivotal role in PD-1 blockade-mediated tumor regression and synergistic anti-tumor effects were observed in combinations of anti-4–1BB with anti-PD-1, we have investigated whether ABL503 (TJ-L14B) synergistically activates tumor-infiltrating lymphocytes (TILs) and inhibits tumor growth when combined with the PD-1 inhibitor, Pembrolizumab, in vitro and in vivo.

Methods To assess the activity of ABL503 (TJ-L14B) and Pembrolizumab in vitro, CD8+ TILs were isolated from patient-derived tumor tissue (hepatocellular carcinoma and ovarian cancer) followed by co-culture with ABL503 (TJ-L14B) and/or Pembrolizumab, along with anti-CD3 stimulation. Following co-culture, the effector function of CD8+ TILs was analyzed by measuring cytokine secretion and proliferation using flow cytometry. The in vivo synergistic anti-tumor efficacy of ABL503 (TJ-L14B) and Pembrolizumab was evaluated in human PD-L1-overexpressing MC38 tumor-bearing human 4–1BB/PD-1/PD-L1 triple knock-in mouse model.

Results We found that ABL503 (TJ-L14B) restored the effector function of 4–1BB+ exhausted CD8+ TILs that were enriched for tumor-specific T cells but unresponsive to the Pembrolizumab. More importantly, the combination of ABL503 (TJ-L14B) and Pembrolizumab significantly further enhanced the functional restoration of human CD8+ TILs compared to Pembrolizumab alone. Consistently, the combination of ABL503 (TJ-L14B) with Pembrolizumab synergistically alleviated tumor growth in the mouse model, with enhanced infiltration and activation of CD8+ TILs in the tumor microenvironment. Moreover, transcriptomic analysis of CD8+ TILs from the mouse model verified that the combination treatment significantly enhanced the activation status of CD8+ TILs.

Conclusions In conclusion, ABL503 (TJ-L14B), PD-L1 and 4–1BB dual-targeting bispecific antibody, elicits a pronounced synergetic tumor growth inhibition with increased infiltration and functionality of exhausted CD8+ T cells which in turn enhance the anti-cancer effects of Pembrolizumab, expecting the therapeutic benefit of ABL503 (TJ-L14B) in combination with PD-1 inhibitors in clinical trials.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.