Abstract 2948: A humanized therapeutic antibody against S100A4 as a novel immune modulator and an inhibitor of cancer metastasis
Authors: Leu Jia-Shiun , Deng Hui , Tran Han Nhat , Salazar Jose Maria , Maldonado Jose A. , Cristobal Carlo D. , Wei Xiong , Lee Hyun-Kyoung , An Zhiqiang , Zhang Ningyan , Yun Kyuson 
Published: April 2023

Abstract
Widespread cancer metastasis still contributes to ~ 90% of cancer-related deaths, and limited progress has been made in treating the metastatic disease. S100A4 is a highly conserved protein and has been demonstrated to promote cancer metastasis and stemness in multiple cancer types. Furthermore, our recent single cell RNA-sequencing analysis of cancer and stromal cells in human gliomas showed that S100A4 is expressed in both cancer and immune cells to promotes immune suppressive tumor microenvironment. Significantly deleting S100A4 function in stromal cells alone was sufficient to reverse the immune phenotypes of glioma associated T cells and myeloid cells, and resulted in significantly extend survival of two different mouse glioma models. Consistently, higher S100A4 expression is also associated with poor outcomes in many cancer types. Together these observations suggest that S100A4 is a promising therapeutic target for multiple cancer types, and we developed and characterized a blocking antibody against human S100A4. We have screened 114 monoclonal antibodies against S100A4 using S100A4-induced chicken neurite outgrowth ex vivo as a functional assay. Seven of the 114 monoclonals showed significant suppressive activity ex vivo and were selected for further analysis for their in vivo activity. We chose two well-characterized breast cancer metastasis models for in vivo screening: MMTV-PyMT spontaneous and 4T1 orthotopic transplantation tumor models. One of the clones, 4-11, showed the most consistent and dramatic lung metastasis suppressive activity in both models. To identify the potential mechanisms of action since the blocking antibody is anticipated to only affect soluble S100A4 function, we focused on potential immune modulatory effect, based on our own study and those of others. We performed flow cytometry to analyze the immune phenotypes in blood, bone marrow, spleen, breast tumor, and lung metastases. In S100A4-11 treated mice, circulating monocytes (CD11b+Ly6gloLy6chi) and tumor-associated CD163+ macrophage frequencies were significantly decreased in both models. In addition, circulating CD4+ T cells and neutrophils (CD11b+Ly6g+Ly6cint) frequencies were also decreased in the 4T1 model. Others have shown that myeloid-derived suppressive cells (MDSC: CD11b+, Ly6gloLy6chi,IAIE-) play an important role in cancer metastasis. Our result suggests that soluble S100A4 protein promotes MDSC polarization or survival in the tumor, peripheral blood, and metastatic lung tissues. These findings strongly suggest that S100A4-11 could be used to block metastasis. We are currently testing the humanized S1004-11 antibody in preparation for clinical studies with this novel immune modulator.
Citation Format: Jia-Shiun Leu, Hui Deng, Han Nhat Tran, Jose Maria Salazar, Jose A. Maldonado, Carlo D. Cristobal, Xiong Wei, Hyun-Kyoung Lee, Zhiqiang An, Ningyan Zhang, Kyuson Yun. A humanized therapeutic antibody against S100A4 as a novel immune modulator and an inhibitor of cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2948.