A Novel Her2/4-1bb Bispecific Antibody, Yh32367 (Abl105) Shows Potent Anti-Tumor Effect Through Tumor-Directed T Cell Activation

4-1BB (TNFSF9, CD137) is a member of the tumor necrosis factor receptor superfamily that functions as a potent costimulator to immune cells, especially T-cell. Although current 4-1BB-targeted strong agonistic antibody exhibit a considerable anti-tumor effect through T cell activation, it has a limitation of liver toxicity. To overcome the challenges of targeting the 4-1BB, we developed a bispecific antibody that can induce tumor-directed T cell activation. A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) targets human epidermal growth factor receptor 2 (HER2) and 4-1BB simultaneously and binds to both targets with high affinity. YH32367 (ABL105) exhibited a strong activation of 4-1BB signal in tumor cells expressing HER2 such as NCI-N87, BT474 and HCC1954 cell lines. In co-culture assay using human peripheral blood mononuclear cell (hPBMC) and HER2-expressing tumor cells, YH32367 (ABL105) stimulated IFN-γ secretion from hPBMC and thereby induced tumor cell lysis. The anti-tumor efficacy of YH32367 (ABL105) was evaluated in HCC1954-bearing hPBMC engrafted humanized mice and MC38/hHER2-bearing h4-1BB knock-in mice. YH32367 (ABL105) had more potent efficacy on tumor growth inhibition in both mouse models compared to the equimolar dosing of trastuzumab. Peripheral T cell increase was not observed in these studies. In particular, YH32367 (ABL105) showed a tumor regression in MC38/hHER2-bearing h4-1BB knock-in mice. In conclusion, YH32367 (ABL105) significantly inhibited tumor growth in a HER2 expression dependent manner and showed potent in vivo efficacy through tumor-directed T cell activation without non-specific systemic T-cell activation. Citation Format: Moo Young Song, Eun-Jung Lee, Hyejin Chung, Yangsoon Lee, Young Bong Park, Min Hyeok Jee, KyeongBae Kim, Mikyeong Ju, Jun Kyung Lee, Byung Hyun Choi, Ju Young Park, DaeWon Kim, Junhwan Kim, Sujin Ahn, Kyoung Kyu Ahn, Kyeongsu Park, Uijung Jung, Wonjun Son, Jaehyun Eom, Eunjung Kim, Donghoon Yeom, Jinhyung Ahn, Daehae Song, Byungje Sung, Weon-kyoo You, Jong Gyun Kim, Se-Woong Oh, Jaeho Jung. A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) shows potent anti-tumor effect through tumor-directed T cell activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6524.