Abstract 6354: The HER2/4-1BB bispecific antibody, YH32367 (ABL105) demonstrates optimal efficacy and safety for HER2-expressing tumors and exhibits synergistic efficacy when combined with anti-PD-L1

Abstract Overexpression/amplification of the human epidermal growth factor receptor 2 (HER2) is associated with clinically aggressive subtypes in various cancers. Currently, new HER2-targeted therapy like trastuzumab deruxtecan have improved outcomes not only for HER2-positive tumors but also for HER2-low tumors. However, curing cancer patients who develop resistance to current HER2-targeted therapies or experience unwanted side effects remains a significant challenge. Therefore, there is a pressing need for more advanced treatments, and one promising approach involves combination with immunotherapy. 4-1BB (CD137) is a key costimulatory receptor expressed on activated T-cells and natural killer cells, making it a promising therapeutic target in cancer. This study presents the anti-tumor efficacy of the HER2/4-1BB bispecific antibody, YH32367 (ABL105), against both HER2-positive and HER2-low tumors. Additionally, the study suggests that YH32367 could be a viable treatment option for combination with anti-PD-1 antibody (Ab). ​ YH32367 has been designed to overcome the challenges with HER2 resistance via tumor-directed 4-1BB agonism. YH32367 induced IFN-γ secretion and thereby eliciting tumor cell death in co-culture condition with hPBMC and HER2-expressing tumor cells. YH32367 showed superior efficacy in eradicating tumors and triggered long-term anti-tumor immunity in MC38/hHER2-bearing h4-1BB KI mouse models, compared to benchmark 4-1BB/HER2-bispecific molecule and anti-HER2 Ab. Even in HER2-low tumor, YH32367 was more effective than benchmark 4-1BB/HER2-bispecific molecule. Additionally, when YH32367 was administered in combination with anti-PD-1 Ab to h4-1BB KI mice bearing HER2-low tumors, a synergistic effect was observed, surpassing the effects of anti-PD-1 Ab alone or anti-HER2 Ab-drug conjugate. The potent anti-tumor efficacy of YH32367 was also verified in HER2 expressing tumor-bearing hPBMC humanized mice. In terms of toxicity, YH32367 demonstrates a favorable safety profile, which was confirmed through a 4-week GLP toxicity study using cynomolgus monkeys at doses of 10, 30, and 100 mg/kg. In summary, YH32367 has demonstrated significant anti-tumor effects, impacting tumor immunity in h4-1BB KI mice with HER2-low and HER2-positive tumors. Furthermore, its combination with anti-PD-1 Ab has shown synergistic efficacy, indicating that YH32367 may offer treatment options not only as a monotherapy but also in combination therapy for HER2 expressing tumors. The phase 1 dose escalation study is currently underway (NCT05523947), and a dose optimization study to determine the recommended phase 2 dose (RP2D) is scheduled for the second half of 2024. Citation Format: Eunjung Lee, Young Bong Park, Minji Choi, Jangwoo Shin, Kyong Bae Kim, Ju Young Park, Junhwan Kim, Kyoung Kyu Ahn, Yangsoon Lee, Kyeongsu Park, Wonjun Son, Donghoon Yeom, Jaehyun Eon, Hanbyul Lee, Hanbyul Jung, Jonghwa Won, Se-Woong Oh, Yeul Hong Kim. The HER2/4-1BB bispecific antibody, YH32367 (ABL105) demonstrates optimal efficacy and safety for HER2-expressing tumors and exhibits synergistic efficacy when combined with anti-PD-L1 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6354.