Bispecific antibody complex pre-targeting and targeted delivery of polymer drug conjugates for imaging and therapy in dual human mammary cancer xenografts: targeted polymer drug conjugates for cancer diagnosis and therapy.

Abstract

INTRODUCTION:

Doxorubicin, a frontline chemotherapeutic agent, limited by its cardiotoxicity and other tissue toxicities, was conjugated to N-terminal DTPA-modified polyglutamic acid (D-Dox-PGA) to produce polymer pro-drug conjugates. D-Dox-PGA or Tc-99 m labeled DTPA-succinyl-polylysine polymers (DSPL) were targeted to HER2-positive human mammary carcinoma (BT-474) in a double xenografted SCID mouse model also hosting HER2-negative human mammary carcinoma (BT-20).

METHODS:

After pretargeting with bispecific anti-HER2-affibody-anti-DTPA-Fab complexes (BAAC), anti-DTPA-Fab or only phosphate buffered saline, D-Dox-PGA or Tc-99 m DSPL were administered. Positive therapeutic control mice were injected with Dox alone at maximum tolerated dose (MTD).

RESULTS:

Only BT-474 lesions were visualized by gamma imaging with Tc-99 m-DSPL; BT-20 lesions were not. Therapeutic efficacy was equivalent in mice pretargeted with BAAC/targeted with D-Dox-PGA to mice treated only with doxorubicin. There was no total body weight (TBW) loss at three times the doxorubicin equivalent MTD with D-Dox-PGA, whereas mice treated with doxorubicin lost 10% of TBW at 2 weeks and 16% after the second MTD injection leading to death of all mice.

CONCLUSIONS:

Our cancer imaging and pretargeted therapeutic approaches are highly target specific, delivering very high specific activity reagents that may result in the development of a novel theranostic application. HER/2 neu specific affibody-anti-DTPA-Fab bispecific antibody pretargeting of HER2 positive human mammary xenografts enabled exquisite targeting of polymers loaded with radioisotopes for molecular imaging and doxorubicin for effective therapy without the associating non-tumor normal tissue toxicities.

• Authors: Ban-An Khaw, Keyur S Gada, Vishwesh Patil, Rajiv Panwar, Savitri Mandapati, Arash Hatefi, Stan Majewski, Andrew Weisenberger
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 41 Issue 8 Pg. 1603-16 (Aug 2014) ISSN: 1619-7089 [Electronic] Germany
• PMID: 24643779 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• Drug Carriers
• Polyglutamic Acid
• Technetium
• Pentetic Acid
• Doxorubicin
• Receptor, ErbB-2

Topics

• Animals
• Antibodies, Bispecific (pharmacokinetics, therapeutic use)
• Carcinoma (diagnostic imaging, radiotherapy)
• Cell Line, Tumor
• Doxorubicin (chemistry, pharmacokinetics, therapeutic use)
• Drug Carriers (chemistry)
• Female
• Humans
• Mammary Neoplasms, Experimental (diagnostic imaging, radiotherapy)
• Mice
• Mice, SCID
• Pentetic Acid (chemistry)
• Polyglutamic Acid (chemistry)
• Radioimmunotherapy
• Radionuclide Imaging
• Receptor, ErbB-2 (immunology)
• Technetium (therapeutic use)
• Tissue Distribution
• Xenograft Model Antitumor Assays