Preclinical Efficacy of the Auristatin-Based Antibody Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors

2016-08-19 14:37:33

AACR Journals  August 19 2016

DOI:  10.1158/0008-5472.CAN-16-0180

Anette Sommer, Charlotte Kopitz, Christoph A. Schatz, Carl F. Nising, Christoph Mahlert,  Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Stefanie Hammer, Simone Greven, Joachim Schuhmacher, Manuela Braun, Ruprecht Zierz, Sabine Wittemer-Rump, Axel Harrenga, Frank Dittmer, Frank Reetz, Heiner Apeler, Rolf Jautelat, Hung Huynh, Karl Ziegelbauer, and Bertolt Kreft


The fibroblast growth factor receptor FGFR2 is overexpressed in a variety of solid tumors, including breast, gastric, and ovarian tumors, where it offers a potential therapeutic target. In this study, we present evidence of the preclinical efficacy of BAY 1187982, a novel antibody–drug conjugate (ADC). It consists of a fully human FGFR2 monoclonal antibody (mAb BAY 1179470), which binds to the FGFR2 isoforms FGFR2-IIIb and FGFR2-IIIc, conjugated through a noncleavable linker to a novel derivative of the microtubule-disrupting cytotoxic drug auristatin (FGFR2-ADC). In FGFR2-expressing cancer cell lines, this FGFR2-ADC exhibited potency in the low nanomolar to subnanomolar range and was more than 100-fold selective against FGFR2-negative cell lines. High expression levels of FGFR2 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro. Pharmacokinetic analyses in mice bearing FGFR2-positive NCIH716 tumors indicated that the toxophore metabolite of FGFR2- ADC was enriched more than 30-fold in tumors compared with healthy tissues. Efficacy studies demonstrated that FGFR2-ADC treatment leads to a significant tumor growth inhibition or tumor regression of cell line–based or patient-derived xenograft models of human gastric or breast cancer. Furthermore, FGFR2 amplification or mRNA overexpression predicted high efficacy in both of these types of in vivo model systems. Taken together, our results strongly support the clinical evaluation of BAY 1187982 in cancer patients and a phase I study (NCT02368951) has been initiated.


Antibody–drug conjugates (ADC) represent a promising therapeutic approach for cancer treatment. These agents combine the specificity of a monoclonal antibody directed against a cell surface antigen with the targeted delivery of a highly potent cytotoxic drug. Stable conjugation and specific targeting result in the accumulation of high local concentrations of cytotoxic agents that would not be tolerable if administered systemically. Currently, there are more than 40 ADCs in phase I/II of clinical development. Most of these contain a microtubule-destabilizing payload, either of the auristatin or the maytansine class. In addition, other payload classes, including DNA targeting pyrrolobenzodiazepines, indolinobenzodiazepine pseudodimers, duocarmycins, calicheamicins, as well as others derived from traditional chemotherapeutics, such as camptothecin and doxorubicin (4, 5), are currently under preclinical and clinical evaluation.

FGFR2 (fibroblast growth factor receptor 2) is a receptor tyrosine kinase with an important role in both embryonic development and tissue repair. Alternative gene splicing of the Cterminal half of the Ig-like domain III yields FGFR2 isoforms IIIb and IIIc exhibiting different ligand-binding specificities as well as distinctive expression profiles. FGFR2 aberrations have been implicated in multiple cancer types, associated with poor prognosis and resistance to cancer treatments. Oncogenic FGFR2 functions, promoted by FGFR2 overexpression, gene amplification, gene fusions, and autoactivating mutations of the receptor, have been described in several cancers, including gastric, breast, and ovarian cancer. FGFR2 gene amplification is found in 4% of triple-negative breast cancers (TNBC) and appears to promote breast tumorigenicity by maintaining breast tumor-initiating cells. In gastric cancer, FGFR2 is amplified in 5% to 10% of tumors, and FGFR2 mRNA overexpression is associated with poor overall survival. Both the prominent expression of FGFR2 in several cancers and the low cell surface expression in normal tissues render FGFR2 a particularly promising target for an ADC.

Empire Genomic's FGFR2 FISH Probe was used in this publication.

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