Abstract 1881: Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-306 targeting IL-13Rα2 in immuno-oncology

Abstract

Abstract Interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed in various types of cancers including glioma and melanoma and is known to be associated with increased tumor invasiveness and metastases. Here, we present the preclinical efficacy and toxicity results for a novel, anti-IL-13Rα2 ADC-LM-306. In vitro binding activity and internalization of LM-306 and LM-106 (unconjugated antibody of LM-306) were assessed in human IL-13Rα2 overexpressing and endogenous cell lines using flow cytometry. The antibody-dependent cell-mediated cytotoxicity (ADCC) and direct cytotoxicity were assessed using viability assays. Cross-species reactivity of drug was assessed in cells expressing cynomolgus, rat and mouse IL-13Rα2. In vivo A375 CDX model was used to assess the effect of LM-306 anti-tumor activity. The toxicity of LM-306 was evaluated in repeated-dose intravenous dose range-finding (DRF) toxicity and single intravenous maximum tolerated dose (MTD) study in cynomolgus monkeys. Both LM-106 and LM-306 showed concentration dependent binding affinity to IL-13Rα2 in various cell lines (Table 1). In addition, LM-106 also showed a dose dependent internalization and ADCC and LM-306 showed significant cytotoxicity in all cell lines (Table 1). Furthermore, LM-306 showed comparable binding affinity to human IL-13Rα2 to its unconjugated counterpart LM-106 (KD:7.43E-10 vs 1.77E-9). LM-306 was also found to be cross-reactive toward cynomolgus IL-13Rα2. In vivo, LM-306 showed tumor growth inhibition at a dose of 1, 3, 10 mg/kg given intravenously once weekly, indicating its strong anti-tumor activity. The highest non-severely toxic dose of LM-306 was determined to be 9 mg/kg in the DRF study and MTD was determined to be 18mg/kg in MTD study for male monkey. In summary, LM-306 showed high binding affinity to human IL13Rα2 expressing cells with potent cytotoxicity in vitro and significant in vivo inhibition of tumor growth, suggesting its therapeutic benefit in immuno-oncology. Summary of parameters of LM-106 and LM-306 binding affinity, internalization, ADCC and cytotoxicity Assay Antibody EC50 (nM) HEK293/H_IL-13Rα2 U251 A375 SKMEL5 Binding affinity LM-106 0.99 0.21 0.57 0.1 LM-306 1.47 0.33 0.8 0.12 Internalization LM-106 2.22 - 0.43 - ADCC LM-106 0.16 - 0.03 - LM-306 0.31 - 0.03 - Cytotoxicity (IC50) LM-306 0.03 0.05 0.01 0.005 Citation Format: Wentao Huang, Zhifang Liu, Yifan Li, Heng Pan, Yuan Li, Xia Qin, Da Fei, Runsheng Li. Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-306 targeting IL-13Rα2 in immuno-oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1881.