Fibroblast growth factor receptor 3 (FGFR3) has been shown to be constitutively activated in bladder, multiple myeloma, non-small cell lung cancer (NSCLC), glioblastoma multiforme, and cervical cancer through overexpression, point mutations, and translocations. In bladder cancer, FGFR3 is typically found to be activated by mutation or over-expression. TCGA data suggests that ~48% of bladder cancer patients harbor FGFR3 mutations such as S249, Y373C and others, as well as fusion proteins of FGFR3 involving transforming acidic coiled-coil gene (TACC3) and FGFR3-BAIAP2L1. LY3076226 is an antibody-drug conjugate (ADC) comprising a fully human anti-FGFR3 antibody, IMC-D11, conjugated to a cytotoxic payload, the maytansine-derivative DM4, via a cleavable linker (sulfo-SPDB). The anti-FGFR3 Ab IMC-D11 recognizes and binds not only wild-type receptor, but also constitutively active mutant receptors and fusion proteins of FGFR3. Preclinical in vitro pharmacodynamics studies have demonstrated that LY3076226 binds to the human FGFR3 protein with high affinity, and following internalization can deliver the potent cytotoxic payload into tumor cells resulting in cell cycle arrest and cell death.
In vivo studies with LY3076226 demonstrated robust antitumor efficacy resulting in tumor stasis or partial or complete tumor responses after 4 weekly doses at 5 mg/kg in bladder cancer cell lines: SW780, RT112 and UMUC-14 that harbor FGFR3-BAIAP2L1, FGFR3-TACC3 fusion or S249C mutation, respectively. We also evaluated over 90 PDXs models using a Modiplex assay and IHC to determine mutational and FGFR3 expression levels. We identified a number of bladder PDX models with R248C, S249 and G370 mutations and a single NSCLC with FGFR3-TACC3, and tested LY3076226 efficacy in these models. Interestingly the incidence of mutations and fusions in these PDX models confirmed prior TCGA results, and confirm that PDX models represent a valuable translational platform for patient tailoring. Similar to RT-112 cell line, LY3076226 significantly inhibited tumor growth in lung PDX model (LXF-2226) with FGFR3-TACC3 fusion resulting in durable complete response in 100% of mice. LY3076226 was also efficacious after 4 weekly treatments at 5 mg/kg, resulting in tumor growth inhibition, tumor stasis or tumor regressions in bladder PDX models with G370C, S249C or R248C FGFR3 mutations, respectively. Additionally, LY3076226 exhibited superior efficacy compared to the naked IMC-D11 Ab or chKTI-ADC controls.
These data support the conclusion that therapy with FGFR3 targeted antibody-drug conjugate LY3076226 may confer tumor control in patients that are FGFR3 positive and harbor FGFR3 mutations or fusion proteins.
Citation Format: David Surguladze, Anthony Pennello, Xiaodi Ren, Tim Mack, Alan Rigby, Paul Balderes, Elizabeth Navarro, Nelusha Amaladas, Scott Eastman, Michael Topper, Yung-mae Yao, Chris Moxham, Gregory Plowman, Dale Ludwig. LY3076226, a novel anti-FGFR3 antibody drug conjugate exhibits potent and durable anti-tumor activity in tumor models harboring FGFR3 mutations or fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4835.
