Abstract 1139: A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) exhibits the optimal efficacy and superior safety profile through tumor-directed 4-1BB agonism
Authors: Lee Eunjung , Chung Hyejin , Lee Yangsoon , Lee Eun-jung , Park Young Bong , Park Ju Young , Ahn Sujin , Kim Junhwan , Ahn Kyoung Kyu , Park Kyeongsu , Son Wonjun , Yeom Donghoon , Jung Jaeho , Won Jonghwa , Oh Se-Woong 
Published: June 2022

Abstract
Although HER2-targeted therapies such as Herceptin® (trastuzumab) have dramatically improved outcomes for solid cancer patients with HER2 overexpression, it remains a challenge to cure the HER2 positive cancer patients with resistance to current HER2-targeted therapies. Therefore, new approaches need to treat them. One approach would be to combine with immunotherapy. 4-1BB (CD137) is a key costimulatory receptor expressed on activated T-cells and natural killer (NK) cells and a promising therapeutic target in cancer. In this study, we present the results from a preclinical study on the efficacy and safety of HER2/4-1BB bispecific antibody, YH32367 (ABL105). YH32367 has been designed to overcome the challenges with HER2 resistance via tumor-directed 4-1BB agonism. Its activity was determined using cell-based 4-1BB bioassay and co-culture assay with human peripheral blood mononuclear cells (hPBMC). In vivo anti-tumor efficacy of YH32367 was assessed in both HER2-expressing tumor-bearing hPBMC humanized mice and h4-1BB knock-in mice. In addition, 4-week repeated dose toxicity study of YH32367 was conducted in cynomolgus monkeys at the dose of 10, 30 and 100 mg/kg. YH32367 stimulated IFN-γ secretion and thereby eliciting tumor cell lysis in co-culture assay with hPBMC and HER2-expressing tumor cells. YH32367 also showed a long-term tumor immunity as well as superior efficacy on tumor eradication in MC38/hHER2-bearing h4-1BB knock-in mouse models, compared to the equimolar dosing of trastuzumab and benchmark 4-1BB agonistic antibody. Even a single dosing of YH32367 at the doses of 1, 3 and 10 mg/kg elicited complete tumor regression in more than 80% of mice bearing MC38/hHER2. In GLP 4-week toxicity study in monkeys, there were no YH32367-related effects on mortality, body weight, hematology, clinical chemistry, urinalysis, microscopic observations, cardiovascular system and immunotyping/cytokine analysis in any doses, indicating a favorable safety profile. In conclusion, YH32367 exhibited potent in vitro and vivo effects via tumor immunity and it was well tolerated and safe in the 4-week toxicity study. These results suggest that YH32367 could be a promising therapeutic for HER2-positive cancer patients, especially with HER2 drug resistance as an effective HER2-targeted therapy. Phase I clinical study is expected to begin in 2022.
Citation Format: Eunjung Lee, Hyejin Chung, Yangsoon Lee, Eun-jung Lee, Young Bong Park, Ju Young Park, Sujin Ahn, Junhwan Kim, Kyoung Kyu Ahn, Kyeongsu Park, Wonjun Son, Donghoon Yeom, Jaeho Jung, Jonghwa Won, Se-Woong Oh. A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) exhibits the optimal efficacy and superior safety profile through tumor-directed 4-1BB agonism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1139.