Advances in epidermal growth factor receptor specific immunotherapy: lessons to be learned from armed antibodies.

Fleury Augustin Nsole Biteghe,Nyangone Ekome Toung Chalomie,Jean De La Croix Ndong,Jean Engohang-Ndong,Stefan Barth,Krupa Naran,Guillaume Vignaux,Neelakshi Mungra,Eden Padayachee

doi:10.18632/oncotarget.27730

Abstract

The epidermal growth factor receptor (EGFR) has been recognized as an important therapeutic target in oncology. It is commonly overexpressed in a variety of solid tumors and is critically involved in cell survival, proliferation, metastasis, and angiogenesis. This multi-dimensional role of EGFR in the progression and aggressiveness of cancer, has evolved from conventional to more targeted therapeutic approaches. With the advent of hybridoma technology and phage display techniques, the first anti-EGFR monoclonal antibodies (mAbs) (Cetuximab and Panitumumab) were developed. Due to major limitations including host immune reactions and poor tumor penetration, these antibodies were modified and used as guiding mechanisms for the specific delivery of readily available chemotherapeutic agents or plants/bacterial toxins, giving rise to antibody-drug conjugates (ADCs) and immunotoxins (ITs), respectively. Continued refinement of ITs led to deimmunization strategies based on depletion of B and T-cell epitopes or substitution of non-human toxins leading to a growing repertoire of human enzymes capable of inducing cell death. Similarly, the modification of classical ADCs has resulted in the first, fully recombinant versions. In this review, we discuss significant advancements in EGFR-targeting immunoconjugates, including ITs and recombinant photoactivable ADCs, which serve as a blueprint for further developments in the evolving domain of cancer immunotherapy.

Highlights

Epidermal growth factor receptor (EGFR) belongs to a family of transmembrane proteins that are known as tyrosine kinases (ErbB family) and made of four members known as: EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4 [1,2,3,4]
EGFR activation begins with ligand binding induced ectodomain dimerization, causing the autotransphosphorylation of tyrosine residues located on the intracellular tyrosine kinase domain [3, 4]
Cancer treatment has been revolutionized by antibody-based therapies that allow for specific targeting of diseased cells

Summary

Introduction

Epidermal growth factor receptor (EGFR) belongs to a family of transmembrane proteins that are known as tyrosine kinases (ErbB family) and made of four members known as: EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4 [1,2,3,4]. EGFR is a 170 kDa glycoprotein, known as HER1 or c-ErbB-1, and was the first member of receptor tyrosine kinase (RTK) to be described [4]. EGFR is characterized by an extracellular ligand www.oncotarget.com binding domain (ectodomain), a single transmembrane domain (TM), and an intracellular domain with tyrosine function [1,2,3]. EGFR activation begins with ligand binding induced ectodomain dimerization (homo- and/or heterodimerization), causing the autotransphosphorylation of tyrosine residues located on the intracellular tyrosine kinase domain [3, 4]. This tyrosinase phosphorylation recruits signal transducers and activators of intracellular substrates such as Rat sarcoma (Ras). Developing new therapeutic approaches that target EGFR, becomes very pertinent

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