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

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.

Development and application of two novel monoclonal antibodies against overexpressed CD26 and integrin α3 in human pancreatic cancer

“…Monoclonal antibodies are excellent agents for use in both diagnosis and therapy of human cancer. The exquisite specificity of the antibodies for the target antigen also makes them ideal tools for investigating the biological, diagnostic, prognostic and predictive value of their target antigens and for use in targeted therapy of human cancers 10,11,23,24 . We have previously reported the generation of two novel anti-CD109 mAbs by means of hybridoma technology using BxPC-3 human pancreatic cancer cells, a cell line derived from a primary tumour, as the source of immunogen 9 .…”

The Therapeutic Potential of Nanobodies

“…Consequently, to improve the effect of antibody therapy, antibodies with moderate affinity towards their antigens are considered more advantageous than high affinity antibodies; the latter can be used as appropriate vehicles for delivery of different agents (e.g., toxins and chemotherapeutics) [23]. As a result of the suboptimal antibody concentrations, many patients also develop resistance to the antibody-based therapies, which leads to additional treatment failure [24].…”

Recent progress in the molecular imaging of therapeutic monoclonal antibodies

“…Therefore, autoimmune diseases may benefit from the success of cancer immunotherapies, and techniques involved in the analysis of mAbs can also allow each to shed light on the other. On the other hand, though therapeutic mAs achieve remarkable clinical success and offer the possibility to treat tumors in a targeted fashion with reduced severe side effects, the responses of different patients vary [ [40] , [41] , [42] ]. Moreover, a significant increase in immune-related adverse events has emerged during cancer immunotherapies [ 43 ].…”