Abstract 3123: Preclinical characterization of AMB302/GQ1011, a first-in-class FGFR3 antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor against diverse FGFR3 overexpression or alteration

Abstract

Abstract Background: Molecular alterations of oncogene FGFR3 in various cancers include FGFR3 gene fusions, activating mutations, and overexpression as a driver mutation. AMB302/GQ1011 is a novel FGFR3-targeting ADC conjugated with an innovative topoisomerase I inhibitor (TopoIx) using intelligent Ligase-Dependent Conjugation (iLDC) technologies developed by GeneQuantum (GQ), providing high homogeneity, excellent druggability, and superior linker stability. Based on preclinical characterization, AMB302/GQ1011 exhibits impressive anti-tumor activities against bladder cancer (BC), head and neck squamous cell carcinoma (HNSCC), and glioblastoma (GBM) with either FGFR3 overexpression or FGFR3 alterations including gene fusions, demonstrating potential as a first-in-class FGFR3 ADC against FGFR3 relevant solid tumor indications. Methods: For biomarker analysis, patient tissue microarrays and tissue blocks were subjected to IHC staining for FGFR3 to assess its real-world intensity. To characterize AMB302/GQ1011, in vitro assays and ex vivo plasma stability were evaluated to confirm the anti-tumor effect and linker stability. In vivo anti-tumor effects of AMB302/GQ1011 were assessed on various CDX and PDX models with FGFR3 overexpression or alterations. The potential toxicity profile of AMB302/GQ1011 was evaluated in NHP via repeated intravenous infusions. Results: AMB302/GQ1011 conjugates a novel FGFR3-targeting antibody (Aimedbio Inc.) with TopoIx (GQ) via a cleavable linker through iLDC platform. In IHC analysis, we detected high and widespread FGFR3 expression in various tumors. In in vitro cytotoxicity assay, AMB302/GQ1011 showed excellent antitumor activity against FGFR3-expressing cells. In various CDX and PDX models with FGFR3 expression or alterations, AMB302/GQ1011 demonstrated superior efficacy compared with benchmark ADCs and FGFR pan-inhibitors. AMB302/GQ1011 dramatically prolonged survival in GBM orthotopic PDX models with F3-T3 fusion by >150% in combination with TMZ. Particularly, in combination with an immune checkpoint inhibitor (ICI), AMB302/GQ1011 exhibited an excellent synergistic antitumor effect. In a monkey toxicity study, AMB302/GQ1011 demonstrated a high tolerability up to 60 mg/kg dosing, without severe adverse effects. Conclusion: AMB302/GQ1011 demonstrated a potent antitumor efficacy in vitro and in vivo models with FGFR3 overexpression and alterations across various solid tumors. Notably, AMB302/GQ1011 suggests the potential for combination with ICI treatment. Moreover, AMB302/GQ1011 exhibited excellent tolerability at high doses in NHP, indicating its safety profile. Our data suggest that AMB302/GQ1011 has potential to become a first-in-class FGFR3-targeting ADC for solid tumors with FGFR3 overexpression or alterations. Citation Format: Byeongkwi Min, Sunghyun Lee, Wonsik Jung, Lina Wang, Yajun Sun, Hyejin Kim, Nam-Gu Her, Paul H. Song, Gang Qin, Do-Hyun Nam. Preclinical characterization of AMB302/GQ1011, a first-in-class FGFR3 antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor against diverse FGFR3 overexpression or alteration [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(6_Suppl):Abstract nr 3123.