Abstract 2137: Development of CAST (cancer stromal targeting) therapy.
Authors: Yasunaga Masahiro , Sugino Takashi , Tsuji Atsushi , Saga Tsuneo , Manabe Shino , Matsumura Yasuhiro 
Published: August 2014

Although many monoclonal antibodies (mAbs) have been already approved for the therapy of cancer, they are usually used in the combination with anticancer agents (ACAs) because of limited anti-tumor activity as single agent. Antibody-drug conjugate (ADC), a next generation of therapeutic antibody, is the promising strategy to enhance the cytotoxic effect. Most human solid tumors, however, possess abundant stroma that hinders the distribution of ADC. Moreover, conventional ADC is depending on the enzymatic cleavage following internalization into the cytoplasm or lysosome. But the process of cell-uptake would be disturbed by stromal barrier. Heterogeneity of the tumor cells also prevents development of the ADC therapy based on cell-specific antigen.

To overcome this drawback, we have created a unique type of ADC, namely CAST (Cancer stromal targeting) therapy, utilizes dense stroma as scaffold for the drug delivery. It was composed of ACAs conjugated to stroma targeting mAb (anti-collagen 4 or anti-fibrin mAb) via PEGylated ester-bond linker. We considered mAb was one of ideal DDS carriers, because IgG in size range from 10 to 20nm had stronger EPR (Enhanced permeability and retention) effect as passive tumor targeting activity than albumin being used in clinics as a carrier. Moreover, our ADC bound to the tumor stroma from which ACAs were control-released gradually and distributed throughout the tumor, resulting in the arrest of tumor growth due to induced damage to both tumor cells and tumor vessels.

In addition to xenograft model, spontaneous mouse cancer models having dense stroma, remarkable fibrin deposition and abundant collagen e.g. chemically-induced cutaneous cancer or pancreatic cancer from genetic engineered mouse were used for the proof concept study of CAST therapy. We also made full use of imaging technology (fluorescence, PET/CT) for the evaluation of the biodistribution property and tumor stroma specificity of our anti-stroma mAbs.

We will present the CAST therapy and discuss our development strategy for the clinical use.

[1] Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechnism of tumoritropic accumulation of proteins and antitumor agent smancs. Cancer Res. 46:6387-92. 1986.

[2] Yasunaga M, Manabe S, Matsumura Y. New concept of cytotoxic immunoconjugate therapy cancer-induced fibrin clots. Cancer Sci. 102:1396-1402, 2011.

[3] Yasuanga M, Manabe S, Tarin D, Matsumura Y. Cancer-stroma targeting therapy by cytotoxic immunoconjugate bound to the collagen 4 network in the tumor tissue. Bioconjugate Chem.22:1776-1783, 2011.

[4] Yasuanga M, Manabe S, Tarin D, Matsumura Y. Tailored immunoconjugate therapy depending on a quantity of tumor stroma. Cancer Sci. 2012. [Epub ahead of print]

[5] Matsumura Y. Cancer stromal targeting (CAST) therapy.Adv Drug Deliv Rev. 64:710-719, 2012.

Citation Format: Masahiro Yasunaga, Takashi Sugino, Atsushi Tsuji, Tsuneo Saga, Shino Manabe, Yasuhiro Matsumura. Development of CAST (cancer stromal targeting) therapy. [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 2137. doi:10.1158/1538-7445.AM2013-2137