ET-05 PRECLINICAL STUDY OF AN ANTI-HUMAN TISSUE FACTOR ANTIBODY-DRUG CONJUGATE IN A MALIGNANT GLIOMA XENOGRAFT MODEL

Whereas macromolecules such as antibody hardly extravasate from normal blood vessels compared with low molecular agents, macromolecules leak from tumor vasculature because of the enhanced permeability. As a result, macromolecules selectively accumulate at tumor sites. We apply this phenomenon, known as the enhanced permeability and retention effect (EPR effect), to drug delivery for cancer therapy. Drug delivery system (DDS) based on the EPR effect is called the passive targeting. On the other hand, DDS based on antigen-antibody or ligand-receptor interaction is the active targeting. Antibody-drug conjugate (ADC), antibody conjugated with antitumor agents, retains both of the passive and active targeting functions. Tissue factor (TF), an initiator in the extrinsic pathway of blood coagulation, is overexpressed in various cancers including malignant glioma. To target the molecule in tumor sites, we have produced several anti-TF monoclonal antibodies. Previously, we evaluated tumor accumulation of an indium-111-labeled anti-TF antibody in an orthotopic glioma xenograft model with high expression of TF by single photon emission computed tomography/computed tomography (SPECT/CT). The imaging study showed that anti-TF antibody significantly accumulated in the tumor compared with control antibody (P < 0.01). The finding suggests that blood-brain barrier in brain tumors is broken and antibodies accumulate in tumors by utilizing both of the passive and active targeting. In this study, to prepare anti-TF ADC, we conjugated monomethyl auristatin E (MMAE), a microtubule inhibitor, to humanized anti-TF antibody. The anti-TF ADC recognized TF expressed in glioma cells and showed potent cytocidal activity against human glioma cell lines depending on TF expression. In addition, we evaluated in vivo antitumor effect of the ADC in a mouse model subcutaneously inoculated with TF-overexpressing glioma cells. Anti-TF ADC showed a significant higher antitumor effect compared with control ADC (P = 0.015).