ADC Development Services Targeting EGFR

Epidermal growth factor receptor (EGFR) is a clinically validated target and often overexpressed in human non-small cell lung cancer (NSCLC), glioblastoma (GBM) as well as head and neck cancer (HNSCC). EGFR ligand-blocking antibodies have been approved for the treatment of these mentioned diseases. Antibody-drug conjugate (ADC) represents an attractive and novel therapy, which directly targets tumour-associated cell-surface antigens and provides targeted cytotoxic drug delivery with improving potency while reducing non-specific cytotoxic effects. With years’ experience in antibody discovery and ADC construction, Creative Biolabs now provides our worldwide customers with a comprehensive set of customized ADC development services targeting EGFR.

Introduction of EGFR

EGFR, also known as HER1/ErbB1, is the founding member of the human EGFR tyrosine kinase family (HER2/ErbB2/Neu, HER3/ErbB3, and HER4/ErbB4). An EGFR monomer consists of an N-terminal ligand-binding extracellular module (ECM) connected to an intracellular module (ICM) by a single-pass transmembrane (TM) helix. EGFR plays a fundamental signaling role in cell growth and is frequently hyper-activated in human cancers via mutation and/or overexpression. EGFR is widely overexpressed in multiple solid tumor types, including NSCLC, GBM, HNSCC, breast cancer, and colorectal cancers. This driving role in malignancies has made EGFR an attractive target for anti-cancer therapy.

Point mutations of the EGFR kinase domain are predominant in NSCLC and GBM. Fig.1 Point mutations of the EGFR kinase domain are predominant in NSCLC and GBM. (Gomez, 2013)

ADC Strategy Targeting EGFR

A clinically proven strategy to treat EGFR driven tumors is to block the EGFR pathway signaling. To this end, monoclonal ligand blocking antibodies as well as EGFR tyrosine kinase inhibitors (TKIs) have been used for the treatment of NSCLC. However, drug resistance is the new challenge to these targeted therapies. Besides, treatment related moderate to severe cutaneous and gastrointestinal toxicities were often observed. Thus, more effective treatment of EGFR positive tumors is needed.

In principle, EGFR-targeted ADCs that rely on target expression and not on inhibition of downstream signaling pathways for activity could circumvent some of these resistance mechanisms of current EGFR inhibitors and be more broadly active. ADCs exploit the binding specificity of monoclonal antibodies (mAbs) as a mechanism for selective delivery of cytotoxic agents to kill tumor cells.


Various EGFR mutations are shown to be tumor-type specific and point mutations in the intracellular portion have been found in the EGFR kinase domain in NSCLC. So far, several ADCs targeting EGFR have been developed. For instance, Cetuximab-vc-PAB-MMAE, composed of a human/mouse chimeric mAb, vc peptide linker, and the tubulin inhibitor auristatin, was designed to specifically target to NSCLC with EGFR gene mutation. This ADC complex can be targeted into A549 human lung cancer xenografts and has obvious cytotoxicity-related inhibition of lung cancer.

Anti-EGFR ADC in Glioblastoma

Patients with GBM have a universally poor prognosis and are in urgent need of effective treatment strategies. Genomic profiling has detected EGFR gene alterations in more than half of GBMs. To date, ADCs targeting EGFR have already been developed to evaluate whether anti-EGFR ADC could be used to treat GBM. Depatuxizumab mafodotin (ABT-414) is an anti-EGFR ADC comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. ABT-414 has been demonstrated promising clinical activity in GBM patients and is currently being evaluated in clinical trials in first-line and recurrent GM disease settings.

Anti-EGFR ADC in Head and Neck Cancer

Dysregulation of EGFR signaling through overexpression of the receptor or hyper-activation of its kinase activity is a common theme in several solid tumors including HNSCC. Beginning with Cetuximab, patients with recurrent and metastatic HNSCC rapidly develop resistance to antibody module. Thus, investigators continue to optimize antibody-related technology to target cell-surface antigens that promote HNSCC growth and novel EGFR-targeting therapies, such as anti-EGFR ADCs. For instance, SHR-A1307, an anti-EGFR ADC, generated from an anti-EGFR antibody with prolonged half-life, and conjugated with a proprietary toxin payload has increased index of EGFR targeting-dependent cytotoxicity. SHR-A1307 has been demonstrated strong and sustained antitumor activities in HNSCC.

What Can We Do for You?

Since EGFR is also widely expressed on a number of normal epithelial tissues, the design of an anti-EGFR ADC requires a careful balance between safety and efficacy. Creative Biolabs takes multiple approaches to mitigate the safety concern while maintaining tumor targeting efficacy of the designed ADC. From the aspect of the whole ADC, a broad distribution of drug/antibody ratio (DAR) can negatively impact both efficacy and safety profiles: low DAR species reduce the potency of ADC while high DAR species are prone to aggregation, increased clearance rate and premature release of the toxic payload during circulation leading to increase off-target toxicity. To circumvent this problem, Creative Biolabs provides various Antibody Design and Conjugation strategies to generate a more homogeneous ADC with increased stability in the circulation, such as lysine conjugation, cysteine conjugation, and enzyme-mediated site-specific conjugation.

 Strategy to develop an effective anti-EGFR ADC. Fig.2 Strategy to develop an effective anti-EGFR ADC. (Wong, 2018)

Moreover, Creative Biolabs has gained significant knowledge in ADC Antibody Screening and extensive experience in DrugLnk™ Custom Synthesis as well as ADC in vivo Analysis and ADC in vitro Analysis. With years of experience in ADC design, production, and analysis, Creative Biolabs is competent to offer you customized ADC development services targeting EGFR. If you are looking for these services right now, please don't hesitate to contact us for more information.


  1. Gomez, G. G.; et al. Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks. Cancer biology & medicine. 2013, 10(4): 192.
  2. Wong, O. K.; et al. RN765C, a low affinity EGFR antibody drug conjugate with potent anti-tumor activity in preclinical solid tumor models. Oncotarget. 2018, 9(71): 33446.

For Research Use Only. NOT FOR CLINICAL USE.

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