Abstract 2641: Tailored antibody drug conjugate (ADC) therapy depending on a quantity of tumor stroma

Abstract

Abstract Although many monoclonal antibodies (mAbs) have been already approved for the therapy of cancer, they are usually used in combination with anticancer agents (ACAs), because of limited anti-tumor activity as single agent. Antibody-drug conjugate (ADC), is a promising next generation therapeutic antibody strategy to enhance the cytotoxic effect. Most human solid tumors, however, possess abundant stroma that hinders the distribution of ADC. Also, heterogeneity of the tumor cells complicates the development of ADC therapy based on cell-specific antigens. Moreover, conventional ADC depends upon enzymatic cleavage of the agent following internalization into the cytoplasm or lysosome and the process of cell-uptake can be diminished by a stromal barrier in fibrotic tumors. To overcome these drawbacks, we have developed stroma-targeting ADCs, namely CAST (Cancer stromal targeting) as a novel type of therapy. SN-38 was conjugated to mAbs against collagen 4, or fibrin via ester-bonds. These ADCs bound to collagen 4 or fibrin networks in the stroma. Sustained release of SN-38 from ADCs diffused throughout the tumor tissue, and caused marked damage to both tumor cells and tumor vessels in a pancreatic cancer model. We also prepared SN-38-conjugated anti-CD 20 mAb via carbamate-bond as a conventional ADC. This cell-targeting ADC enabled SN-38 to be released by a carboxylesterase inside of the tumor cell following internalization and showed strong anti-tumor activity against malignant lymphoma which is a hypervascular and stroma poor tumor type. Our results indicate that the conjugate-design, in parallel with the choice of targeting antibodies, should be selected to maximize the therapeutic effect in each individual tumor depending upon the quantity of its stromal component. We will present data on this novel tailored antibody drug conjugate (ADC) therapy and discuss our development strategy for its clinical use. [1] Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism 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] Matsumura Y. Cancer stromal targeting (CAST) therapy.Adv Drug Deliv Rev. 64:710-719, 2012. [5] Yasuanga M, Manabe S, Tarin D, Matsumura Y. Tailored immunoconjugate therapy depending on a quantity of tumor stroma. Cancer Sci. 104:231-7, 2013. [6] Hisada Y, Yasunaga M, Hanaoka S, Saijou S, Sugino T, Tsuji A, Saga T, Tsumoto K, Manabe S, Kuroda J, Kuratsu J, Matsumura Y. Discovery of an uncovered region in fibrin clots and its clinical significance. Sci Rep. 3:2604, 2013. Citation Format: Masahiro Yasunaga, Shino Manabe, David Tarin, Yasuhiro Matsumura. Tailored antibody drug conjugate (ADC) therapy depending on a quantity of tumor stroma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2641. doi:10.1158/1538-7445.AM2014-2641