Abstract
Radiation-inducible neo-antigens are proteins expressed on cancer cell surface after exposure to ionizing radiation (IR). These neo-antigens provide opportunities to specifically target cancers while sparing normal tissues. Tax interacting protein-1 (TIP-1) is induced by irradiation and is translocated to the surface of cancer cells. We have developed a monoclonal antibody, 2C6F3, against TIP-1.Epitope mapping revealed that 2C6F3 binds to the QPVTAVVQRV epitope of the TIP-1 protein. 2C6F3 binds to the surface of lung cancer (A549, LLC) and glioma (D54, GL261) cell lines. 2C6F3 binds specifically to TIP-1 and ELISA analysis showed that unconjugated 2C6F3 efficiently blocked binding of radiolabeled 2C6F3 to purified TIP-1 protein. To study in vivo tumor binding, we injected near infrared (NIR) fluorochrome-conjugated 2C6F3 via tail vein in mice bearing subcutaneous LLC and GL261 heterotopic tumors. The NIR images indicated that 2C6F3 bound specifically to irradiated LLC and GL261 tumors, with little or no binding in un-irradiated tumors.We also determined the specificity of 2C6F3 to bind tumors in vivo using SPECT/CT imaging. 2C6F3 was conjugated with diethylene triamine penta acetic acid (DTPA) chelator and radiolabeled with 111Indium (111In). SPECT/CT imaging revealed that 111In-2C6F3 bound more to the irradiated LLC tumors compared to un-irradiated tumors. Furthermore, injection of DTPA-2C6F3 labeled with the therapeutic radioisotope, 90Y, (90Y-DTPA-2C6F3) significantly delayed LLC tumor growth. 2C6F3 mediated antibody dependent cell-mediated cytotoxicity (ADCC) and antibody dependent cell-mediated phagocytosis (ADCP) in vitro.In conclusion, the monoclonal antibody 2C6F3 binds specifically to TIP-1 on cancer and radio-immunoconjugated 2C6F3 improves tumor control.
Highlights
Tumor-specific targeted drug delivery has the potential to improve the efficacy of cytotoxic agents against tumors while minimizing toxicity to normal tissues
We evaluated the cytosolic induction of Tax interacting protein-1 (TIP-1) protein after irradiation
We found induction of TIP-1 at 24 h and 48 h in irradiated A549, D54 and Lewis lung cancer (LLC) cells when compared to sham alone
Summary
Tumor-specific targeted drug delivery has the potential to improve the efficacy of cytotoxic agents against tumors while minimizing toxicity to normal tissues. MAbs achieve therapeutic effects by (i) antagonizing the receptor signaling or turnover directly (ii) affecting the vasculature or stroma indirectly or (iii) invoking an immune response through activation of complement-dependent cytotoxicity or antibody-dependent cellular toxicity [1, 2]. Antibodies recognizing biomarkers expressed on the surface of the cancer cells or the tumor vasculature have been successfully used in the clinic. These include bevacizumab that targets VEGF, cetuximab that targets EGFR, pembrolizumab that targets PD1 (T cells), ipilimumab that targets CTLA4 (T cells) www.impactjournals.com/oncotarget and trastuzumab that targets HER2 [4, 5]. TIP-1’s involvement in many different cancer pathways demonstrates its potential to be explored as a molecular target for cancer therapy
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