Abstract
Therapeutic antibodies used to treat cancer are effective in patients with advanced-stage disease. For example, antibodies that activate T-lymphocytes improve survival in many cancer subtypes. In addition, antibody–drug conjugates effectively target cytotoxic agents that are specific to cancer. This review discusses radiation-inducible antigens, which are stress-regulated proteins that are over-expressed in cancer. These inducible cell surface proteins become accessible to antibody binding during the cellular response to genotoxic stress. The lead antigens are induced in all histologic subtypes and nearly all advanced-stage cancers, but show little to no expression in normal tissues. Inducible antigens are exploited by using therapeutic antibodies that bind specifically to these stress-regulated proteins. Antibodies that bind to the inducible antigens GRP78 and TIP1 enhance the efficacy of radiotherapy in preclinical cancer models. The conjugation of cytotoxic drugs to the antibodies further improves cancer response. This review focuses on the use of radiotherapy to control the cancer-specific binding of therapeutic antibodies and antibody–drug conjugates.
Highlights
Examples of the therapeutic uses of antibodies to treat cancer include unconjugated therapeutic antibodies that block the function of the target proteins such as EGFR and PD-L1 on the surface of cancer cells [1,2]
The first radiation-inducible proteins identified include cell adhesion molecules [11,12]. These inducible proteins are not well suited for antibody development because their expression is limited to microvascular endothelial cells but not on cancer cells, and some are shed from cancer cells
Antibodies to the radiation-inducible proteins glucose-regulated protein 78 (GRP78) and tax-interacting protein-1 (TIP1) enhance the cytotoxic effects of radiotherapy and improve survival in mouse models of cancer [15]
Summary
Examples of the therapeutic uses of antibodies to treat cancer include unconjugated (naked) therapeutic antibodies that block the function of the target proteins such as EGFR and PD-L1 on the surface of cancer cells [1,2]. The cytotoxic agents are released following endocytosis of the antibody– drug conjugate into cancer cells [3–5]. Cancer neoantigens contain mutations that are specific to cancer (e.g., mutations in EGFR) [7]. Another example is over-expressed cancer antigens such as her2/neu or CD20 [7]. Intra-tumoral heterogeneity can be a limitation, wherein the antigen is not present on every cell within a tumor, or the antigen might be inaccessible to antibody binding. Overcoming these limitations of cancer antigens can improve the therapeutic antibody treatment of cancer
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