ADCs Against Lung Cancer: PI

In recent years, nanotechnology and nanotherapy have exerted a profound impact on many fields of medicine, of which the biggest contribution in cancer is mainly derived from the development of new drug delivery systems, including liposomes, nanoparticles, and antibody-drug conjugates (ADCs). Antibody-drug conjugate is a new type of engineered anti-cancer drug that consists of a recombinant monoclonal antibody (mAb) covalently bound to cytotoxic compound (payload) and targets tumor-associated antigens. Its advantage is that ADC combines the high selectivity of monoclonal antibody with the high titer (0.3-1 kDa) of cytotoxic drugs, and the IC50 value is in the sub-nanomolar range, thereby overcoming the limitations of traditional chemotherapy and targeted therapy. The ADCs (https://www.creative-biolabs.com/adc/) that have been approved by the regulatory authorities include Brentuximab Vidotin for CD30-positive Hodgkin's lymphoma and Enmetrastuzumab for HER2-positive metastatic breast cancer. These two ADCs set a milestone in the treatment of hematological malignancies and solid tumors, paving the way for multiple clinical trials evaluating new ADCs in different tumors including lung cancer.

Lung cancer is the most common cause of cancer-associated death. In the past ten years, the model of lung cancer treatment has undergone fundamental changes, which is due to the identification of carcinogenic factors and thereafter the development of effective targeted therapies. Despite these progresses, most patients with advanced lung cancer develop acquired resistance to targeted therapies, while others show intrinsic primary resistance. ADCs preferentially target tumor cells expressing specific targets, providing a new therapeutic orientation to the biological treatment of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

ADC MOA
ADCs work as self-targeting nanoscale carriers, which overcome the limitations of traditional synthetic nanomedicines, such as lack of delivery to target cells, low cell internalization rate, and high clearance rate. ADCs exert their anti-cancer activity through different mechanisms, including induction of apoptosis, antibody-dependent cytotoxicity (ADCC), and/or complement-dependent cytotoxicity (CDCC). After binding to the target antigen, ADC is internalized in clathrin-coated endosomes. One of the mechanisms by which ADCs exert their anti-tumor effects is to induce cell apoptosis. When the tumor-associated antigens are kinase receptors or other molecules that actively participate in signal transduction, this special mechanism occurs. The abnormal activation of HER2 promotes the proliferation of cancer cells by up-regulating gene expression. Some intracellular signaling pathways, such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and RAS/RAF/extracellular signal-regulated kinase (ERK) can be effectively inhibited by ADCs targeting HER2.

ADCs for the treatment of NSCLC (https://www.creative-biolabs.com/adc/adc-development-for-nsclc.htm)
NSCLC is the most common malignant tumor of the chest, with the highest mortality rate among all cancers. The most common histological variants of NSCLC include adenocarcinoma (AC) and squamous cell carcinoma (SqCC). In recent years, molecular biology research has allowed us to identify a subgroup of patients with specific gene mutations, including epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) gene rearrangement. If patients have these operable genetic changes, they can be treated with tyrosine kinase inhibitors (TKIs). Similarly, current investigation shows that some ADCs can target other molecules that are overexpressed in NSCLC cells.

ADC targeting HER2
HER2 is a member of the receptor tyrosine kinase (RTK) EGFR family and is encoded by the erb-b2 receptor tyrosine kinase 2 (ERBB2) gene located in the chromosomal region 17q11.2-q12. After ligand-receptor binding, RTK may homodimerize or heterodimerize with other family members, thereby activating different downstream molecular pathways. Heterodimers containing HER2 can mediate an effective oncogenic signal due to their high affinity and specificity for various ligands and their slow separation from growth factors. Although there is no approved HER2 targeted therapy in NSCLC, the biological relevance of HER2 as a carcinogenic driver of NSCLC has prompted the development of some drugs, including two ADCs, namely (T-DM1) and (DS-8201a).

* TDM-1, Kadcyla, ado-trastuzumab emtansine
* Trastuzumab deruxtecan (DS-8201a)