Abstract 3091: Response of C4.4A-positive patient-derived xenograft models of ESCC, HNSCC and bladder cancer to BAY1129980, a C4.4A-targeted antibody drug conjugate
Authors: Willuda Joerg , Pena Carol , Kneip Christoph , Carrigan Patricia E. , Lerchen Hans-Georg , Linden Lars , Kreft Bertolt D. 
Published: July 2017

Abstract
C4.4A (LYPD3) is a cancer- and metastasis-associated transmembrane cell surface protein which is expressed at high frequency and density in multiple tumor types including squamous and non-squamous non-small cell lung carcinoma ((NSCLC), head & neck squamous cell carcinoma (HNSCC), esophageal squamous cell carcinoma (ESCC) and bladder cancer. C4.4A expression is restricted to a limited number of tissues (e.g. suprabasal layer of skin) making C4.4A an attractive target for the treatment of cancer with a C4.4A-targeted antibody-drug conjugate (ADC). BAY 1129980 (C4.4A-ADC), is an ADC consisting of a fully human C4.4A-targeting monoclonal antibody (technology licensed from BioInvent) conjugated via a novel, non-cleavable alkyl hydrazide linker to a novel, highly potent auristatin W, an antimitotic agent (technology licensed from Seattle Genetics, Inc.). This C4.4A-ADC has been previously shown to be efficacious in C4.4A positive cell line-derived and PDX models of NSCLC. Here we present new preclinical efficacy data of C4.4A-ADC in patient-derived xenograft (PDX) models of ESCC, HNSCC and bladder cancer. Models were selected based on tumor C4.4A levels as determined by mRNA levels and immunohistochemistry (IHC), the latter of which allowed ranking of models according to H-score, percentage of C4.4A positivity, and staining intensity (0 to 3+) in the cell membrane. Representative C4.4A-positive models were selected for in vivo efficacy studies (n=7 each): 4 HNSCC, 4 ESCC and 2 bladder cancers. C4.4A-ADC was administered as one cycle (Q4Dx3) at doses of 7.5 and 15 mg/kg, and efficacy was assessed up to 4 weeks post treatment for optimum tumor growth inhibition (TGI). In ESCC models a response to C4.4A ADC was seen in ES0190 (TGI of 77%; 15mg/kg) and in ES0195 (59%). In HNSCC models an ADC effect on tumor growth was observed in HN10847 (46%), HN9619 (34%), and HN10321 (22%). Finally, both bladder models tested were sensitive to treatment, with a transient response seen in BL0597 (41%) and a strong and complete tumor growth control in BL5001 (93%,) which was superior to cisplatin. The data show that C4.4A-positive PDX models of ESCC, HNSCC and bladder cancer can respond to C4.4A-ADC. C4.4A expression served as a marker for preselection of the models. Nevertheless, other factors may affect response and sensitivity of these tumor models, such as sensitivity to tubulin inhibition, ADC uptake and intracellular processing. In summary, these data support further exploration of the potential of BAY 1129980 in HNSCC, ESCC and bladder cancer in addition to NSCLC. A Phase 1 clinical trial of BAY 1129980 is ongoing (NCT02134197).
Citation Format: Joerg Willuda, Carol Pena, Christoph Kneip, Patricia E. Carrigan, Hans-Georg Lerchen, Lars Linden, Bertolt D. Kreft. Response of C4.4A-positive patient-derived xenograft models of ESCC, HNSCC and bladder cancer to BAY1129980, a C4.4A-targeted antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3091. doi:10.1158/1538-7445.AM2017-3091