Bypassing the Binding Site Barrier

Brandon Bordeau

Competitive Inhibition Increases Monoclonal Antibody Distribution in Solid Tumors .

Competitive inhibition increases monoclonal antibody distribution in solid tumors.

Graduate Student Project

Introduction

Monoclonal antibodies (mAbs) are called "Magic Bullets", but for a magic bullet to work, it has to hit its target.My name is Brandon Bordeau, and I am a Ph.D. candidate in Dr. Balthasars laboratory in the pharmaceutical sciences department at the University of Buffalo, and my research focuses on improving antibody uptake and penetration in solid tumors.  In solid tumors, there is a large number of "targets" or antigens, and cells that are close to blood vessels -the point of entry for mAbs into the tumor space-- get "first dibs" on binding to mAb, leading to an overkilling effect on cells near blood vessels at the expense of limited tumor cell killing in other tumor regions. This phenomenon is referred to as the binding site barrier and contributes to poor mAb efficacy in solid tumors. Currently, there is not a practical approach to overcome the binding site barrier to improve mAb efficacy in solid tumors. My project aimed to develop competitive inhibitors that block the mAb: target interaction, for a short period, to increase mAb tumor penetration, and, as a result, increase the number of cancer cells exposed to therapeutic mAb. 

Abstract

Poor penetration of monoclonal antibodies (mAbs) in solid tumors is explained by the binding site barrier hypothesis. Following extravasation, mAbs rapidly bind to cellular antigens, leading to the observation that therapeutic antibody in solid tumors is localized around tumor vasculature. Our group developed a strategy to increase antibody tumor penetration through transient competitive inhibition of mAb-antigen binding. A model competitive inhibitor (CI) was developed for experimental validation of the CI hypothesis. The tumor distribution of mAb administered alone or in-complex with CI to xenograft bearing mice was evaluated with fluorescence microscopy. Co-administration of CI with mAb led to 50% increase in mAb tumor penetration. CI co-administration significantly increased the efficacy of an FDA approved mAb therapy in xenograft bearing mice. These results support the hypothesis that transient competitive inhibition can improve therapeutic antibody distribution in solid tumors and enhance antibody efficacy.

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