Anti-tax interacting protein-1 (TIP-1) monoclonal antibody targets human cancers

Heping Yan; Vaishali Kapoor; Kim Nguyen; Walter J. Akers; Hua Li; Jalen Scott; Richard Laforest; Buck Rogers; Dinesh Thotala; Dennis Hallahan

doi:10.18632/oncotarget.9713

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Research Papers:

Anti-tax interacting protein-1 (TIP-1) monoclonal antibody targets human cancers

Heping Yan, Vaishali Kapoor, Kim Nguyen, Walter J. Akers, Hua Li, Jalen Scott, Richard Laforest, Buck Rogers, Dinesh Thotala and Dennis Hallahan _

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Oncotarget. 2016; 7:43352-43362. https://doi.org/10.18632/oncotarget.9713

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Abstract

Heping Yan1,*, Vaishali Kapoor1,*, Kim Nguyen1, Walter J. Akers2,3, Hua Li1, Jalen Scott1, Richard Laforest2, Buck Rogers1, Dinesh Thotala1,3 Dennis Hallahan1,2,3

1Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri, USA

2Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, Missouri, USA

3Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA

*Co-first authors

Correspondence to:

Dennis Hallahan, email: [email protected]

Keywords: TIP-1, radiation-inducible, monoclonal antibody, radioimmunotherapy, in vivo imaging

Received: March 11, 2016 Accepted: May 13, 2016 Published: May 30, 2016

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.

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Research Papers:

Anti-tax interacting protein-1 (TIP-1) monoclonal antibody targets human cancers

Abstract