ADCs Against Lung Cancer: PII

ADC targeting Trop-2

Trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein encoded by the tumor-associated calcium signal transducer 2 (TACSTD2) gene located in the 1p32 region of chromosome, and is a new target for the treatment of solid tumors.It acts as a calcium signal sensor. After binding to ligands such as insulin growth factor-1 (Igf-1), Trop-2 promotes the release of intracellular calcium and activates the ERK/mitogen-activated protein kinase (MAPK) pathway, thereby promoting cell survival. Unlike other oncogenes, Trop-2 overexpression has nothing to do with changes in gene structure, but is the result of dysregulation of the complex network of transcription factors, including inactivation of p63 and forkhead box protein p3 (FOXP3). Importantly, a recent meta-analysis of 16 studies (including 2 NSCLC cohorts) showed that tumor Trop-2 overexpression is associated with reduced survival and poor prognosis. These data indicate that targeting Trop-2 plays a key role in lung cancer biology and may be a promising method for the treatment of NSCLC and SCLC.

• Sacituzumab govitecan (IMMU-132)

ADC targeting c-MET

Mesenchymal epithelial transformation is an RTK encoded by the MET proto-oncogene, located in the 7q21-31 region of chromosome, and is closely related to tumor biology. It is expressed in various normal tissues, whose ligand is hepatocyte growth factor (HGF). Ligand binding induces c-MET dimerization and activates MAPK, PI3K/AKT, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) downstream pathways, promoting cell survival, proliferation, and invasion. The overexpression of c-MET is associated with poorly differentiated histology and plays a key role in ADC selectivity. Regarding the key role of MET in lung cancer biology, whether as a driver of primary cancer or as a driver of acquired drug resistance (such as EGFR-TKIs and ALK-TKIs), some MET inhibitors are under active research, including TKIs and ADCs.

• Telisotuzumab vedotin (ABBV-399)
• SHR-A1403

ADC targeting PTK7

Protein tyrosine kinase 7 (PTK7, also known as colon cancer kinase-4, CCK4) is a catalytically-inactive RTK-like protein, which was firstly discovered in colon cancer. It acts as a switch co-receptor in the canonical and non-canonical Wnt, semaphorin/plexin, and vascular endothelial growth factor receptor 1 (VEGFR1) pathways, which are involved in cell communication, planar cell polarity, and migration during embryogenesis and adult tissue homeostasis. Depending on the receptor environment, the expression of PTK7 has been reported to be up-regulated in certain tumors, such as colorectal cancer, esophageal squamous cell carcinoma, and gastric cancer, or down-regulated in other tumors, such as renal cell carcinoma and melanoma. PTK7 was previously reported to be down-regulated in SqCC and AC, and was associated with a better prognosis of AC. Therefore, it has received more and more attention as a potential therapeutic target for NSCLC.

• PF-06647020 (PF-7020)

ADC targeting ALCAM/CD166

The activated leukocyte adhesion molecule (CD166) is encoded by the CD166 gene located in the 3q13.11 region of chromosome. It is a type 1 transmembrane glycoprotein that is expressed in neurons, fibroblasts, endothelial cells, and keratinocytes. It mediates the adhesion between homophilic (CD166-CD166) and heterophilic (CD166-CD6) cells, and participates in cell migration processes involving neuronal development, hematopoiesis, epithelial morphogenesis, and inflammation. It can activate metalloproteinases and promote tumor proliferation, invasion, and metastasis, of which the overexpression is related to the poor prognosis of a wide range of solid tumors (including melanoma, mesothelioma, colorectal cancer, esophageal squamous cell carcinoma, and endometrial cancer). The data on NSCLC is contradictory. In fact, some studies have reported that CD166 expression is significantly associated with smaller tumor size and no lymph node metastasis, while other studies have reported that CD166 expression is significantly associated with shortened survival.

• CX-2009

ADC targeting NaPi2b

Type IIb sodium-dependent phosphate transporter is a multi-pass transmembrane protein responsible for the electro-cotransportation of phosphate and sodium in epithelial cells. It is encoded by the SLC34A2 gene of chromosome region 4p15.2, an interesting therapeutic target in cancer treatment. In lung tissue, NaPi2b participates in the synthesis of surfactants by alveolar type II cells, which is highly expressed in NSCLC, papillary thyroid carcinoma, and non-mucinous ovarian cancer. In NSCLC, the high expression level of NaPi2b has also been shown to be related to AC histology, the presence of EGFR mutations, and a better prognosis. NaPi2b targeted drugs, including ADC, are under clinical research on solid tumors.

• XMT-1536

ADC targeting AXL

AXL is a member of the RTK family called TAM, which is encoded by the AXL gene located in the chromosome region 19q13.2. AXL is activated by growth inhibition specific protein 6 (GAS-6) or by gas 6 independent mechanisms, such as RTK, which is overexpressed in many tumor types such as lung cancer, breast cancer, thyroid cancer, and ovarian cancer, and promotes the activation of PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT signaling pathways. In the NSCLC model, the down-regulation of AXL leads to an increase in the expression of E-cadherin, thereby increasing cell adhesion and inhibiting tumor cell migration. On the other hand, AXL overexpression promotes resistance to chemotherapy, targeted therapy, and immunotherapy. Selective and multi-target AXL inhibitors, such as sunitinib and cabosantan IB, have been approved for the treatment of non-thoracic cancer, while other AXL inhibitors are under clinical research. Since AXL is highly expressed on lung cancer cell membranes, it is an attractive target for ADCs and is currently being developed and tested in early clinical trials.

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