Monoclonal antibody therapy of solid tumors: clinical limitations and novel strategies to enhance treatment efficacy

Abstract

Monoclonal antibodies (mAbs) have become a cornerstone in the therapeutic guidelines of a wide range of solid tumors. The targeted nature of these biotherapeutics has improved treatment outcomes by offering enhanced specificity to reduce severe side effects experienced with conventional chemotherapy. Notwithstanding, poor tumor tissue penetration and the heterogeneous distribution achieved therein are prominent drawbacks that hamper the clinical efficacy of therapeutic antibodies. Failure to deliver efficacious doses throughout the tumor can lead to treatment failure and the development of acquired resistance mechanisms. Comprehending the morphological and physiological characteristics of solid tumors and their microenvironment that affect tumor penetration and distribution is a key requirement to improve clinical outcomes and realize the full potential of monoclonal antibodies in oncology. This review summarizes the essential architectural characteristics of solid tumors that obstruct macromolecule penetration into the targeted tissue following systemic delivery. It further describes mechanisms of resistance elucidated for blockbuster antibodies for which extensive clinical data exists, as a way to illustrate various modes in which cancer cells can overcome the anticancer activity of therapeutic antibodies. Thereafter, it describes novel strategies designed to improve clinical outcomes of mAbs by increasing potency and/or improving tumor delivery; focusing on the recent clinical success and growing clinical pipeline of antibody-drug conjugates, immune checkpoint inhibitors and nanoparticle-based delivery systems.

Keywords: antibody therapy; antibody–drug conjugates; immune checkpoint inhibitors; nanoparticle delivery vehicles; treatment resistance.

Figure 1

Structural features of the tumor microenvironment that increase interstitial pressure and hinder mAb extravasation and distribution. (A) Blood vessels that irrigate healthy normal tissue possess a continuous inner lining of endothelial cells, enveloped by perivascular cells called pericytes that grant integrity to the vascular tube. The extracellular matrix (ECM) contains a lax network of collagen and proteoglycan fibers, and the presence of macrophages and fibroblasts is scarce. Lymph vessels efficiently remove and prevent the accumulation of macromolecules and interstitial fluid. (B) Increased demand of oxygen and nutrients in tumor tissues causes blood vessels to form defectively and irregularly shaped. The lack of pericytes makes the vascular tube unstable and leaky. The abundant presence of fibroblasts and infiltrating macrophages promote the formation of a dense ECM, with a condensed network of collagen and proteoglycan fibers. The paucity of lymph vessels leads to the accumulation of macromolecules and an increase in interstitial fluid pressure (IFP). The fibrotic nature of the ECM and the altered pressure differential between the vascular lumen and the tumor hinder antibody convection into the targeted tissue.

Figure 2

Structural components of an antibody–drug conjugate. Trastuzumab emtansine is a commercially approved anti-Her2 antibody with a potent maytansinoid payload attached to lysines in the mAb polypeptide chain through a non-cleavable linker.

Figure 3

CTLA-4 and PD1/PD-L1 blockade using immune checkpoint inhibitors. Dendritic cells process and present tumor neoantigens through the MHC to the TCR on T-cells in the draining lymph nodes. T-cell activation further requires a co-stimulatory signal by CD80-CD28 binding. Upon T-cell activation, CTLA-4 can be upregulated in T-cells. CTLA-4 has a higher affinity towards CD80 than CD28; therefore, the overexpression of CTLA-4 interferes with the co-stimulatory CD80-CD28 signal preventing T-cell activation. Ipilimumab prevents this mechanism by binding to CTLA-4 thus blocking its interaction with CD80. Once activated T-cells migrate to the tumor to mount an immune anti-tumor response, tumor cells and macrophages can upregulate PD-L1 and suppress the immune response by interacting with the upregulated PD-1 on T-cells. Anti-PD1 and anti-PD-L1 antibodies inhibit this adaptive immune resistance mechanism. Abbreviations: CTLA-4, cytotoxic T-lymphocyte-associated antigen; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; MHC, major histocompatibility complex; TCR, T cell receptor.

Figure 4

Harnessing the EPR effect to improve tumor delivery using nanoparticle carriers. Blood vessels that irrigate the tumor tissue are defective. The lack of pericytes and altered structural features make the vessels less stable and leaky. Larger fenestrations between the endothelial cells allow nanoparticles to extravasate into the tumor. The fibrotic extracellular matrix lacks proper lymphatic drainage, therefore, nanoparticles can accumulate in the tissue following extravasation (passive targeting). Nanoparticles (NP) can be functionalized with monoclonal antibodies, or other active targeting agents, to promote specific internalization and drug delivery into targeted cells (cancer cells or other cells in the tumor microenvironment) once they accumulate in the tumor through passive targeting.