Please use this identifier to cite or link to this item:
Scopus Web of Science® Altmetric
Type: Journal article
Title: APOMAB antibody-drug conjugates targeting dead tumor cells are effective in vivo
Author: Staudacher, A.H.
Li, Y.
Liapis, V.
Hou, J.J.C.
Chin, D.
Dolezal, O.
Adams, T.E.
van Berkel, P.H.
Brown, M.P.
Citation: Molecular Cancer Therapeutics, 2019; 18(2):335-345
Publisher: American Association for Cancer Research
Issue Date: 2019
ISSN: 1535-7163
Statement of
Alexander H. Staudacher, Yanrui Li, Vasilios Liapis, Jeff Jia Cheng Hou, David Chin, Olan Dolezal, Timothy E. Adams, Patrick H. van Berkel and Michael P. Brown
Abstract: Antibody-drug conjugates (ADC) have revolutionized the field of cancer therapy. ADCs combine the high specificity of tumor-targeting monoclonal antibodies with potent cytotoxic drugs, which cannot be used alone because of their high toxicity. Till date, all ADCs have either targeted cell membrane proteins on tumors or the tumor vasculature and microenvironment. Here, we investigate ADCs of APOMAB (DAB4, or its chimeric derivative, chDAB4), which is a mAb targeting the La/SSB protein, which is only accessible for binding in dying or dead cancer cells. We show that DAB4-labeled dead cells are phagocytosed by macrophages, and that the apoptotic/necrotic areas within lung tumor xenografts are bound by DAB4 and are infiltrated with macrophages. We show that only DAB4-ADCs with a cleavable linker and diffusible drug are effective in two lung cancer models, particularly when given after chemotherapy. These results are consistent with other recent studies showing that direct internalization of ADCs by target cells is not essential for ADC activity because the linker can be cleaved extracellularly or through other mechanisms. Rather than targeting a tumor cell type specific antigen, DAB4-ADCs have the advantage of targeting a common trait in most solid tumors: an excess of post-apoptotic, necrotic cells either adjacent to hypoxic tumor regions or distributed more generally after cytotoxic therapy. Consequently, any antitumor effects are solely the result of bystander killing, either through internalization of the dead, ADC-bound tumor cells by macrophages, or extracellular cleavage of the ADC in the tumor microenvironment.
Keywords: Cell Line, Tumor
Lung Neoplasms
Antibodies, Monoclonal
Xenograft Model Antitumor Assays
Tumor Microenvironment
RAW 264.7 Cells
A549 Cells
Description: "Published first November 9, 2018."
Rights: ©2018 American Association for Cancer Research.
DOI: 10.1158/1535-7163.MCT-18-0842
Grant ID:
Appears in Collections:Aurora harvest 8
Medicine publications

Files in This Item:
There are no files associated with this item.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.