Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

Abstract

Despite the significant resources dedicated to the development of monoclonal antibody (mAb) therapies for solid tumors, the clinical success, thus far, has been modest. Limited efficacy of mAb in solid tumors likely relates to unique aspects of tumor physiology. Solid tumors have an aberrant vasculature and a dense extracellular matrix that slow both the convective and diffusive transport of mAbs into and within tumors. For mAbs that are directed against cellular antigens, high antigen expression and rapid antigen turnover can result in perivascular cells binding to and eliminating a significant amount of extravasated mAb, limiting mAb distribution to portions of the tumor that are distant from functional vessels. Many preclinical investigations have reported strategies to improve mAb uptake and distribution; however, to our knowledge, none have translated into the clinic. Here, we provide an overview of several barriers in solid tumors that limit mAb uptake and distribution and discuss approaches that have been utilized to overcome these barriers in preclinical studies.

Keywords: Solid tumors; antibody uptake and distribution; antibody–drug conjugate; monoclonal antibody.

Figure 1

Shown is a graphic representation of barriers that limit therapeutic antibody uptake and distribution into solid tumors and the approaches that have been reported to mitigate the tumor barriers. A graphic key is provided in the bottom left inset. Figure 1 was created using BioRender.com.