Development of Antibody-Drug Conjugates Using DDS and Molecular Imaging.

Masahiro Yasunaga,Atsushi Tsuji,Koretsugu Ogata,Tsuneo Saga,Masaru Furuta,Shino Manabe,Yasuhiro Matsumura,Yoshikatsu Koga

doi:10.3390/bioengineering4030078

Abstract

Antibody-drug conjugate (ADC), as a next generation of antibody therapeutics, is a combination of an antibody and a drug connected via a specialized linker. ADC has four action steps: systemic circulation, the enhanced permeability and retention (EPR) effect, penetration within the tumor tissue, and action on cells, such as through drug delivery system (DDS) drugs. An antibody with a size of about 10 nm has the same capacity for passive targeting as some DDS carriers, depending on the EPR effect. In addition, some antibodies are capable of active targeting. A linker is stable in the bloodstream but should release drugs efficiently in the tumor cells or their microenvironment. Thus, the linker technology is actually a typical controlled release technology in DDS. Here, we focused on molecular imaging. Fluorescent and positron emission tomography (PET) imaging is useful for the visualization and evaluation of antibody delivery in terms of passive and active targeting in the systemic circulation and in tumors. To evaluate the controlled release of the ADC in the targeted area, a mass spectrometry imaging (MSI) with a mass microscope, to visualize the drug released from ADC, was used. As a result, we succeeded in confirming the significant anti-tumor activity of anti-fibrin, or anti-tissue factor-ADC, in preclinical settings by using DDS and molecular imaging.

Highlights

Antibody-drug conjugate (ADC) is a generation therapeutic antibody
T-DM1 is effective for patients with HER2-positive advanced or remnant breast cancer previously treated with standard dugs, including the naked anti-HER2 antibody [10,11]
By using in vivo imaging, we found that specific Fab showed the same tumor accumulation as non-specific IgG (Figure 2a). These results indicated the importance of molecular imaging for observing antibody delivery in vivo

Summary

Introduction

Antibody-drug conjugate (ADC) is a generation therapeutic antibody. Several ADCs have been used in clinics already [1,2,3,4]. T-DM1 is effective for patients with HER2-positive advanced or remnant breast cancer previously treated with standard dugs, including the naked anti-HER2 antibody [10,11]. Recent advances in bioengineering have improved these drawbacks, resulting in the emergence of second generation ADCs. Since many methods have been used to improve both the stability in the bloodstream and the controlled drug release in the targets, which has led to demonstrating clinical effectiveness, including SGN-35, anti-CD30 chimeric antibody (human constant regions with down-sized mouse variable regions) with monomethyl auristatin E (MMAE, IC50; nM level) via valine-citrulline (cathepsin cleavable) linker and T-DM1, anti-HER2 humanized antibody (largely human component with minimized mouse CDR segment) with Maytansine (IC50; nM level) via a thioester (noncleavable) linker, which have lower immunogenicity [1,2,5,10]. An evaluation and modification of antibody delivery and controlled drug release is important for ADC development

Antibody Delivery and the EPR Effect

Immuno-PET Imaging

Conclusions