Abstract 1234: An antibody-drug conjugate targeting tissue factor with broad anti-tumor efficacy in xenograft models with heterogeneous tissue factor expression.

Abstract

Abstract Tissue factor (TF) is aberrantly expressed in a wide variety of solid tumors, and expression has been associated with poor prognosis. In normal physiology, TF is the main initiator of the coagulation cascade, which starts when circulating factor VII(a) (FVII(a)) binds membrane bound TF. The TF:FVIIa complex proteolytically activates FX to generate FXa, eventually resulting in clot formation. In addition, the TF:FVIIa complex activates PAR-2 intracellular signaling, thereby stimulating the production of pro-angiogenic factors, cytokines and adhesion molecules. We developed an antibody-drug conjugate (ADC) composed of a human TF-specific IgG1κ antibody (TF-011), a protease-cleavable valine-citrulline (vc) linker and the microtubule disrupting agent monomethyl auristatin E (MMAE). Unconjugated TF-011 efficiently inhibited TF:FVIIa induced ERK phosphorylation and IL-8 production, but showed only minor inhibition of FXa generation or clot formation. Unconjugated TF-011 efficiently killed TF-positive tumor cells by antibody dependent cell-mediated cytotoxicity (ADCC) in vitro, and showed some anti-tumor efficacy in vivo in a prophylactic setting. Upon target binding, TF-011 was rapidly internalized and co-localization with LAMP-1 was observed already after 1 hour. This suggests efficient lysosomal targeting, a prerequisite for intracellular release of MMAE and subsequent tumor cell killing by an ADC. Indeed, TF-011-vcMMAE efficiently induced tumor cell killing in vitro, which was dependent on and correlated with TF cell surface expression. In addition, TF-011-vcMMAE demonstrated potent anti-tumor efficacy in xenograft models for pancreatic and epidermoid cancer in vivo. Therapeutic treatment at doses as low as 0,3 mg/kg inhibited tumor growth, whereas tumor regression was observed at doses of 1 mg/kg or higher. Importantly, TF-011-vcMMAE also induced tumor cell killing in human biopsy-derived xenograft models, which are thought to represent the genetic and histological heterogeneity of human tumors. Immunohistochemical analysis confirmed that the heterogeneity of TF expression in human tumors was reflected in human biopsy-derived xenografts. TF-011-vcMMAE induced efficient tumor regression in xenograft models for bladder, lung, pancreatic, prostate, ovarian and cervical cancer, with the percentage of TF positive cells ranging from 25-50% to 75-100%. In two tumor models that showed TF expression in less than 25% of tumor cells, TF-011-vcMMAE showed inhibition of tumor growth. In summary, TF-011-vcMMAE is a promising new ADC that showed potent anti-tumor activity in vivo in a wide variety of models, including models that represent the heterogeneous TF expression that is observed in human tumors. The ADC potently kills tumor cells by disrupting microtubules, while preserving the effector functions of the unconjugated antibody. Citation Format: Esther C.W. Breij, David Satijn, Sandra Verploegen, Bart E. de Goeij, Danita H. Schuurhuis, Mischa Houtkamp, Wim K. Bleeker, Paul W. Parren. An antibody-drug conjugate targeting tissue factor with broad anti-tumor efficacy in xenograft models with heterogeneous tissue factor expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1234. doi:10.1158/1538-7445.AM2013-1234