The epidermal growth factor receptor (EGFR) belongs to the tyrosine kinase receptors family and is present in the epithelial cell membrane. Its endogenous activation occurs through the binding of different endogenous ligands, including the epidermal growth factor (EGF), leading to signaling cascades able to maintain normal cellular functions. Currently, antibody-drug conjugates (ADCs) have been extensively researched to combine the chemotherapeutic agent toxicity and specific target for EGFR overexpressing tumor tissues.
The development of ADCs that combine monoclonal antibodies with the cytotoxic effects of chemotherapy has shown promising efficacy with limited toxicities, and also shown great potential for the lung cancer treatment currently. BOC Sciences is one of the leaders in biotherapeutic drug development. Our comprehensive ADCs system offers a wide range of ADCs design and construction services for various cancers. As your value-added partner in biopharmaceutical drug development, we offer a complete range of ADCs construction services targeting EGFR.
Epidermal growth factor receptor (EGFR) is a trans-membrane glycoprotein, consisting of extracellular ligand-binding domain and cytoplasmatic tyrosine kinase domain. EGFR family involve four distinct members with common structural elements including EGFR (HER1/ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). Each member of the EGFR family acts as a key mediator in cell signaling pathways involving cell proliferation, apoptosis, angiogenesis, and metastatic spread. For example, the EGFR/ligand binding (including epidermal growth factor (EGF) and transforming growth factor (TGF)) result in the activation of inactive receptors by homo- or hetero-dimerization, which facilitates the phosphorylation of intracellular tyrosine kinase domain, initiation of downstream signaling pathways and ends up in the cell proliferation and inhibition of apoptosis. Pathologically, EGFR signaling overexpression extensively facilitates tumor progression and leads to promote proliferation and apoptosis inhibition. EGFR dysregulation is observed in a vast number of tumors such as head, neck, breast, lung, colorectal, prostate, kidney, pancreas, ovary, and brain cancers. Hence, EGFR has been recognized as the strong and rational target in the treatment of cancers.
Fig. 1. Schematic of epidermal growth factor receptor (EGFR) trafficking (Seminars in Cancer Biology. 2022, 1044-579X).
As EGFR is known as the key player in the regulation and activation of important cellular processes, the development of molecular agents targeting EGFR signaling pathway is a well-known strategy for the design of promising anti-cancer drugs. For example, depatuxizumab mafodotin is an EGFR-targeting antibody drug conjugate consisting of the monoclonal antibody 806 linked through a non-cleavable linker to a toxic payload, monomethyl auristatin F (MMAF). Mechanistically, MMAF binds to tubulins, disrupts microtubule dynamics and subsequently induces G2/M arrest and cell death. The extracellular domain of EGFR is composed of two cysteine-poor homologous large domains and two cysteine-rich domains. The epitope recognized by ABT-806 is located on the first cysteine-rich domain of the EGFR extracellular domain. This epitope is masked in the inactive tethered monomer state (tethered) or in the active ligand-bound back-to-back dimer state. A phase I clinical study demonstrated that depatuxizumab mafodotin exhibits potent cytotoxic activity against glioblastoma patient-derived xenograft models expressing high levels of either wild type EGFR or EGFRvIII.
EGFR-Targeted Therapy in Lung Cancer
Lung cancer is the leading cause of oncological deaths worldwide. Regardless of the continuous advances in diagnosis and multimodality therapies, the prognosis remains poor with 5-year overall survival rates. Lung cancer is characterized by the accumulation of multiple genetic and epigenetic alterations, including somatic mutations, and genecopy number gains, that result in the activation of oncogenes or inactivation of tumor suppressor genes. Lung cancer is subdivided into non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC, which is further divided into three subtypes (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma), presents with frequent deregulation of the EGFR signaling particularly in the adenocarcinoma subtype, which is instead rarely observed in SCLC. Thence, EGFR-targeted therapies have become the frontline treatment for NSCLC.
Fig. 2. Lung cancer cells.
ADCs can selectively deliver cytotoxic drugs to cancer cells to increase the percentage of drug molecules, thus lowering the minimum effective dose and increasing the maximum tolerated dose. EGFR-focused targeted therapy has promoted dramatic changes to the treatment model and research philosophy of lung cancer. EGFR-targeted therapy is a precision approach aimed at treating patients with regimens tailored to the unique molecular profile of their respective cancers. BOC Sciences has extensive experience in ADCs development with expertise in linker-payload production and bioconjugate screening and modification. We now provide a full range of ADCs preparation services for cancer treatment with developed and mature conjugation protocols. BOC Sciences' custom conjugation services allow the generation of high quality conjugates optimized to meet your specifications, and we promise to provide stable, reproducible conjugates efficiently within a minimal timescale.