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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

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

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.

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Disclosure of potential conflicts of interest

B.A. Khaw is a co-founder of Akrivis Technologies, LLC. No potential conflicts of interest were disclosed by other co-authors.

Authors’ contributions

Concepts and design: B.A. Khaw, K. Gada, V. Patil, R. Panwar

Development of methodology: B.A. Khaw, K. Gada, V. Patil, R. Panwar, S. Mandapati

Acquisition of data: B.A. Khaw, K. Gada, V. Patil, R. Panwar, S. Mandapati

Analysis and interpretation of data: B.A. Khaw, K. Gada, V. Patil, R. Panwar

Writing, review and/or revision of the manuscript: B.A. Khaw, K. Gada, V. Patil, R. Panwar

Material support: A. Hatefi, S. Majewski, Andrew Weissenberger.

Grant support

This work was supported by B.A. Khaw’s unrestricted research account.

Financial support

Partial support from unrestricted grant from Gwathmey Inc., and Discretionary account of Dr. Khaw’s laboratory.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Bouve College of Health Sciences, School of Pharmacy, Northeastern University, 140 The Fenway, Rm X138, 130 Huntington Ave, Boston, MA, 02115, USA

    Ban-An Khaw, Keyur S. Gada, Vishwesh Patil, Rajiv Panwar & Savitri Mandapati

  2. Department of Pharmaceutics, Rutgers University, New Brunswick, NJ, USA

    Arash Hatefi

  3. Department of Radiology, West Virginia University, Morgantown, WV, USA

    Stan Majewski

  4. Jefferson Lab, Thomas Jefferson National Accelerator Facility, 12000 Jefferson Avenue, Newport News, VA, 23606, USA

    Andrew Weisenberger

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  1. Ban-An Khaw
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Correspondence to Ban-An Khaw.

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Khaw, BA., Gada, K.S., Patil, V. et al. Bispecific antibody complex pre-targeting and targeted delivery of polymer drug conjugates for imaging and therapy in dual human mammary cancer xenografts. Eur J Nucl Med Mol Imaging 41, 1603–1616 (2014). https://doi.org/10.1007/s00259-014-2738-2

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  • DOI: https://doi.org/10.1007/s00259-014-2738-2

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