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892 ABL503 (TJ-L14B), PD-L1x4–1BB bispecific antibody induces superior anti-tumor activity by PD-L1-dependent 4–1BB activation with the increase of 4–1BB+CD8+ T cells in tumor microenvironment
  1. Uijung Jung1,
  2. Jaehyoung Jeon1,
  3. Shinai Lee1,
  4. Hyung-Seung Jin2,
  5. Youngkwang Kim1,
  6. Eunsil Sung1,
  7. Hyunjoo Kim1,
  8. Yangmi Lim1,
  9. Jonghwa Won1,
  10. Zhengyi Wang3,
  11. Wenqing Jiang3,
  12. Jaeho Jung1 and
  13. Gihoon You1
  1. 1ABL Bio Inc., Seongnam, Korea, Republic of
  2. 2Asan Medical Center, Seoul, Korea, Republic of
  3. 3I-Mab Biopharma, Shanghai, China


Background PD-(L)1 inhibitor has revolutionized cancer treatment, but there are unmet clinical needs for PD-(L)1 inhibitor-resistant/refractory patients. Activation of T cells in tumor microenvironment by 4-1BB agonist antibodies is one of the promising approaches to complement the current limitation of PD-(L)1 inhibitors. Although 4-1BB is a promising target for immunotherapy, clinical studies using 4-1BB agonist antibodies showed systemic immune cell activation resulting in dose-limiting hepatotoxicity. We generated ABL503 (TJ-L14B), a bispecific antibody that combines PD-(L)1 blockade and PD-L1-dependent 4-1BB agonistic activity by binding both PD-L1 and 4-1BB to limit unwanted toxicities while exerting a potent anti-tumor efficacy. Here, we reported the pre-clinical properties of ABL503 (TJ-L14B) in various studies.

Methods The activity of ABL503 (TJ-L14B) was characterized and evaluated in 1) PD-1 and 4-1BB signaling reporter cells cocultured with various tumor cells and PBMCs, 2) hPD-L1/h4-1BB knock-in mice implanted with MC38 tumor expressing different level of hPD-L1, 3) patient-derived lung cancer organoids cocultured with autologous PBMCs, and 4) PBMCs from healthy donors to measure cytokine release.

Results Functional evaluation of ABL503 (TJ-L14B) indicates the activation of 4-1BB signaling was solely dependent on engagement of hPD-L1 expressed on immune cells as well as on tumor cells, pointing to pivotal roles of PD-L1 on both immune cells and tumor cells for the activity of ABL503 (TJ-L14B). In vivo anti-tumor activity of ABL503 (TJ-L14B) across different hPD-L1 levels showed prominent anti-tumor effect with significantly increased number of CD8+ cells and 4-1BB+ cells in the tumor. This anti-tumor activity was correlated with the proliferation (Ki-67+) of CD8+ T cells in the tumor microenvironment. Ex vivo assays utilizing patient-derived lung cancer organoids revealed that ABL503 (TJ-L14B) exhibits superior tumor-killing activity than that by benchmark PD-L1 antibody, Atezolizumab. In addition, cytokine release assay demonstrated that ABL503 (TJ-L14B) did not induce non-specific pro-inflammatory cytokine release by human PBMCs.

Conclusions Our data indicate that PD-L1 and 4-1BB dual targeting bispecific antibody, ABL503 (TJ-L14B), shows potent 4-1BB agonistic activity and anti-tumor effect in a PD-L1-dependent fashion concomitant with 4-1BB+/CD8+ T cell activation and proliferation to overcome limitations of PD-(L)1-targeted therapy while minimizing the risk of peripheral toxicity. The phase 1 clinical trial in the U.S. is currently ongoing in patients with locally advanced or metastatic solid tumors (NCT04762641).

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