Engaging innate immunity for targeting the epidermal growth factor receptor: Therapeutic options leveraging innate immunity versus adaptive immunity versus inhibition of signaling

Abstract

The epidermal growth factor receptor (EGFR) is a key player in the normal tissue physiology and the pathology of cancer. Therapeutic approaches have now been developed to target oncogenic genetic aberrations of EGFR, found in a subset of tumors, and to take advantage of overexpression of EGFR in tumors. The development of small-molecule inhibitors and anti-EGFR antibodies targeting EGFR activation have resulted in effective but limited treatment options for patients with mutated or wild-type EGFR-expressing cancers, while therapeutic approaches that deploy effectors of the adaptive or innate immune system are still undergoing development. This review discusses EGFR-targeting therapies acting through distinct molecular mechanisms to destroy EGFR-expressing cancer cells. The focus is on the successes and limitations of therapies targeting the activation of EGFR versus those that exploit the cytotoxic T cells and innate immune cells to target EGFR-expressing cancer cells. Moreover, we discuss alternative approaches that may have the potential to overcome limitations of current therapies; in particular the innate cell engagers are discussed. Furthermore, this review highlights the potential to combine innate cell engagers with immunotherapies, to maximize their effectiveness, or with unspecific cell therapies, to convert them into tumor-specific agents.

Selection of bispecific antibodies with optimal developability using FcRn‑pH‑HPLC as an optimized FcRn affinity chromatography method

“…Bispecific and multispecific antibodies are increasingly being developed as potential treatments for cancers. 59 , 60 As these antibodies contain multiple antigen‑binding domains, which can be incorporated as various different structures and orientations within the bi- or multispecific format, the effects of altering the type of antigen-binding domain structure used, or increasing the number of antigen-binding domains, and of altering where they occur within the molecule on FcRn binding is becoming increasingly relevant. Further study may be required to elucidate why these modifications affect the FcRn dissociation pH of a bsAb.…”

Immunotherapeutic progress and application of bispecific antibody in cancer

“…It uses the Triomab molecular pattern and relies on two antigen-binding arms to bind the CD3 site of cytotoxic T cells and the EpCAM site of tumor cells respectively, thereby guiding T cells to kill target cells ( 131 – 133 ). The bsAb AFM24 developed by Affimed targets EGFR and CD16A located on innate immune cells and can bind and redirect innate immune cells such as NK cells and macrophages to EGFR + tumor cells ( 134 ), thereby directly killing tumor cells. AFM24 is effective against a variety of EGFR-expressing tumor cells regardless of EGFR expression level and KRAS/BRAF mutation status ( 135 ).…”

Gene expression biomarkers differentiate overall survival of colorectal cancer upon targeted therapies

“…These patients were treated with either cetuximab or bevacizumab in combination with chemotherapy (FOLFOX or FOLFIRI). Cetuximab targets the epidermal growth factor receptor (EGFR) and in uences immune cells, including natural killer (NK) cells and macrophages 5 . In contrast, bevacizumab targets vascular endothelial growth factor (VEGF) and inhibits tumor angiogenesis.…”