Abstract 1680: In vitro and in vivo activity of a highly potent and novel FGFR2/FGFR4 dual targeting antibody-drug conjugate
Authors: Meyer Matthew J. , Jenkins David , Batt David , Mosher Rebecca , Isaacs Randi , Hu Tiancen , Capka Vladimir , Zhang Xiamei , Chen Dongshu , Tang Lujia , Daley Mike , Nowakowski Patrycja , Shim Yeonju , Jiang Wei , Ettenberg Seth , Lees Emma 
Published: August 2015

The fibroblast growth receptors 2 and 4 (FGFR2, FGFR4) are overexpressed in a broad spectrum of malignancies. In a subset of breast, gastric, and esophageal cancers, increased FGFR2 expression is driven by FGFR2 copy number (CN) gain, which renders these tumors dependent on FGFR2 pathway activation and is associated with poor prognosis. FGFR4 expression is increased in response to both FGFR4 CN gain, as seen in embryonal rhabdomyosarcoma, or by the PAX3-FOXO1 fusion gene product which transcriptionally activates FGFR4, as seen in alveolar rhabdomyosarcoma. Additionally, other mechanisms drive increased FGFR2 expression, e.g. in subsets of lung and breast cancer, and increased FGFR4 expression, e.g. in subsets of hepatocellular, breast, and pancreatic cancer. This elevated expression in malignancies combined with the observation that FGFR2 and FGFR4 are efficiently internalized upon antibody binding make both receptors attractive targets for antibody-drug conjugate (ADC) therapy. To this end, a drug discovery campaign was initiated and a novel, highly potent FGFR2, FGFR4 dual targeting ADC was discovered. This ADC consists of a fully human antibody (discovered in collaboration with MorphoSys) conjugated to the potent maytansine-derived microtubule-disruptor, DM1, via an SMCC non-cleavable thioether linkage (linker payload technology licensed from ImmunoGen, Inc.). In vitro, the ADC is active against FGFR2 and FGFR4 positive cells in viability assays and is efficiently processed yielding the principle catabolite Lys-SMCC-DM1. In vivo, the ADC is highly efficacious against a variety of disease relevant xenograft models including FGFR2 amplified breast and gastric models and a PAX3-FOXO1 translocation positive alveolar rhabdomyosarcoma model. Additionally, the ADC is potent against a subset of primary tumor derived breast and lung xenograft models that lack FGFR2 CN gain or the PAX3-FOX01 translocation. Consistent with the molecule's mode of action, anti-tumor activity is preceded by G2/M cell cycle arrest and apoptosis. Taken together these data suggest that this novel, dual targeting ADC may be an effective treatment for patients with FGFR2 or FGFR4 positive tumors including, but not limited to those with FGFR2 CN gain or the PAX3-FOXO1 fusion gene.

Citation Format: Matthew J. Meyer, David Jenkins, David Batt, Rebecca Mosher, Randi Isaacs, Tiancen Hu, Vladimir Capka, Xiamei Zhang, Dongshu Chen, Lujia Tang, Mike Daley, Patrycja Nowakowski, Yeonju Shim, Wei Jiang, Seth Ettenberg, Emma Lees. In vitro and in vivo activity of a highly potent and novel FGFR2/FGFR4 dual targeting antibody-drug conjugate. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1680. doi:10.1158/1538-7445.AM2015-1680