1058 YH32364 (ABL104), a novel EGFR/4–1BB bispecific antibody exhibits potent antitumor efficacy with an excellent safety profile

• DOI: 10.1136/jitc-2022-sitc2022.1058
• Publication Date: 2022-11-08T01:16:32Z
• Authors: Eunjung Lee; Hyejin Chung; Yangsoon Lee; Young Bong Park; Eun-Jung Lee; Hyunmo Koo; Mikyeong Ju; Ju Young Park; Sujin Ahn; Junhwan Kim; Kyeongsu Park; Wonjun Son; Jaehyun Eom; Hanbyul Lee; Jaeho Jung; Jonghwa Won; Se-Woong Oh
• Keywords: CD137; Cancer Immunotherapy

<h3>Background</h3> Epidermal growth factor receptor (EGFR) is a key in cellular proliferation, differentiation, and survival, which has been considered as main target the treatment of malignancies. Although with EGFR-targeted therapy chemotherapy improved outcomes for EGFR overexpressing cancer, its clinical application limited due to drug resistance. Therefore, there an urgent <i>unmet</i> medical <i>need new</i> therapies that can <i>overcome resistance</i>, particularly cancer. Combination immunotherapy would be one new options resolve 4-1BB (CD137) costimulatory expressed on activated T cells natural killer (NK) cells, promising therapeutic A novel YH32364 (ABL104) generated overcome challenges EGFR-drug resistance via tumor-directed agonism signal blocking. <h3>Methods</h3> EGFR/4-1BB-bispecific antibody engineered IgG1 isotype. Its activity was determined using cell-based bioassay co-culture assay human peripheral blood mononuclear (hPBMC). <i>In vivo</i> anti-tumor efficacy infiltrated-immune into tumor were assessed h4-1BB knock -in (KI) mice models. Three-week repeated dose toxicity study range finding (DRF) conducted cynomolgus monkeys at 30 100 mg/kg. <h3>Results</h3> binds high affinity. not only blocked signaling but also indicated by IFN-γ secretion, leading cell lysis hPBMC EGFR-expressing cells. exhibited superior regression immunity MC38/hEGFR-bearing KI mouse models, compared equimolar dosing cetuximab. 3</i>-week monkey<i>,</i> no YH32364-related toxicological findings including skin toxicity, mortality, body weight, hematology, chemistry etc., indicating favorable safety profile. <h3>Conclusions</h3> potent <i>in vitro</i> and<i> it well tolerated safe potentially tumor-localized activation. These results suggest could EGFR-overexpressing cancer patients, especially