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

Authors Cruz E, Kayser V

Received 24 February 2019

Accepted for publication 10 April 2019

Published 1 May 2019 Volume 2019:13 Pages 33—51

DOI https://doi.org/10.2147/BTT.S166310

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Melinda Thomas

Peer reviewer comments 4

Editor who approved publication: Dr Doris Benbrook


Esteban Cruz, Veysel Kayser

School of Pharmacy, The University of Sydney, Sydney, NSW, Australia

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, treatment resistance, antibody–drug conjugates, immune checkpoint inhibitors, nanoparticle delivery vehicles

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