In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents. Up to now, there are 15 approved ADC drugs worldwide, involving targets such as HER2, Trop-2, Nectin-4, CD19, CD22 and BCMA, etc.
Nectins are Ca2+-independent immunoglobulin superfamily cell adhesion molecules that contribute to various cell-cell adhesions and are overexpressed in a variety of human malignancies. At present, only one Nectin-4 ADC drug, Padcev (enfortumab vedotin), has been approved for marketing for the second-line treatment of patients with uroepithelial cancer.
Struture of Nectin-4
Nectin-4, a type I transmembrane cell adhesion molecule belonging to the Nectin family, was formerly known as a homologue of the poliovirus receptor (PVR/CD155), also known as the poliovirus receptor-related (PRR) protein.
The ectodomain of Nectin-4 consists of three lg-like domains, a single transmembrane domain, and a cytoplasmic tail region that binds afadin, an anchor protein that links Nectin-4 to actin filaments.
Figure 1. Structure of Nectin-4 
Nectin-4, together with cadherins, is involved in the formation and maintenance of adhesive junctions; it also interacts with TIGIT in immune regulation; and, in addition, is involved in host-pathogen interactions, and thus would be a potential target for measles virus-based lysosomal therapies.
Figure 2. b The interplay between Nectin-4 and cadherins at the site of cell–cell adhesions. c Interaction of Nectin-4 and TIGIT. 
Nectin-4 is strongly expressed in fetal tissues during development. There is little or no expression in adult tissues, besides the placenta, throat, bladder, breast, stomach, esophagus, salivary gland (ducts), and skin (epidermis and sweat glands).
By contrast, it was observed that Nectin-4 is overexpressed in various types of tumors (e.g., colorectal, gastric, esophageal, urotherial, breast, ovarian, hepatocellular, non-small cell lung carcinoma, and renal papillary cell). Nectin-4 can promote tumor cell proliferation and differentiation, angiogenesis, lymphangiogenesis and lymphatic metastasis through activation of the PI3K/AKT pathway, and plays an important role in cancer development and metastasis. Its role as an oncogene is being investigated.
Approved Nectin-4 ADC: Padcev
Compared to popular ADC targets such as HER2, Trop2 and EGFR, there are fewer targeted agents for Nectin-4, with only one ADC product, Padcev (enfortumab vedotin), approved for marketing worldwide.
Padcev (enfortumab vedotin) is the first ADC drug developed by Seattle Genetics/Astellas that targets Nectin-4, a cell surface protein highly expressed in urothelial cancer. Padcev utilizes Seattle Genetics’ proprietary ADC technology and consists of enfortumab, a human IgG1 monoclonal antibody targeting Nectin-4, and MMAE, a microtubule disrupting agent, linked by a cleavable dipeptide linker.
Figure 3. Structure of Padcev 
In December 2019, Padcev was granted accelerated approval by the FDA for the treatment of adult patients with locally advanced or metastatic urothelial cancer.
In July 2021, the FDA grants regular approval to Padcev for locally advanced or metastatic urothelial cancer and also expanded its indication for patients with locally advanced or metastatic uroepithelial cancer who have been previously treated with a PD-1/PD-L1 inhibitor and are not eligible for cisplatin therapy.
In April 2022, Padcev was approved for marketing in the EU, and in addition to Europe, Padcev is currently approved for marketing in Japan.
In April 2023, the FDA granted accelerated approval for Keytruda in combination with Padcev for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who are not eligible for cisplatin-containing chemotherapy.
Padcev has rapidly opened up the market since its full FDA approval in 2021, with global sales of $757 million in 2022 and $466 million in the first half of 2023.
Nectin-4 ADC in Clinical Trials
Most Nectin-4 ADCs are currently in the early development stage.
|9MW-2821||Mabwell||Solid Tumor, UC, CC, PC, HER2- BC, NSCLC||Phase 2|
|CRB-701 (SYS6002)||Corbus Pharmaceuticals|
|Solid Tumor, UC, BC, PC||Phase 1|
|SKB410||Kelun-Biotech||Solid Tumor||Phase 1|
|BAT-8007||BAT-8007||Solid Tumor||Phase 1|
|BT8009||Bicycle Therapeutics||Solid Tumor, UC||Phase 1/2|
|CAT-13||Catalent CTS Inc||Solid Tumor||IND|
|JS-114||Junshi Bio||Solid Tumor||IND|
|NTX-1105||Nectin Therapeutics Ltd||Solid Tumor||IND|
|Etx-22||Emergence Therapeutics AG||Solid Tumor||IND|
Table. Nectin-4 ADC in Clinical Trials
9MW2821 is China's first, global second Nectin-4 targeted ADC approved for clinical study. The multiple ongoing clinical studies include more than 10 different solid tumors (eg. urothelial carcinoma, cervical carcinoma, prostate cancer, HER-2 negative breast cancer and non-small cell lung cancer), evaluate safety, tolerability, pharmacokinetics, and preliminary antitumor activity.
9MW2821 is a novel Nectin-4-targeting ADC based on inter-chain site specific conjugate technology, composed of specially designed linker, novel antibody molecule, and the cytotoxic drug MMAE. The homogeneous drug-antibody ratio and novel linker of 9MW2821 improves the stability of the conjugate in systemic circulation, enabling efficient drug delivery and avoiding off-target toxicity.
Figure 4. 9MW2821 structure 
Utilising the CSPC Pharmaceutical’s proprietary enzyme-catalyzed site-specific antibody conjugation technology, SYS6002 is able to direct the potent mitotic inhibitor MMAE specifically to Nectin-4 expressing cancer cells. The stability of the linker can also facilitate the delivery of high concentration of MMAE into the tumor and reduce side effects with the decrease in undesirable systemic exposure.
In February 2023, Corbus Pharmaceuticals and CSPC Megalith Biopharmaceutical have entered an exclusive licensing agreement for CRB-701 (SYS6002). Under the deal, Corbus Pharmaceuticals will have exclusive rights to develop and commercialise CRB-701 in Canada, Australia, the UK, the EU (including the European Free Trade Area), and the US, while CSPC will retain SYS6002’s rights in the remaining markets.
BT8009 is a Bicycle Toxin Conjugate (BTC) in which a Nectin-4 binding Bicycle® (bicyclic peptide) is conjugated via an inert sarcosine spacer chain, and a cleavable linker, to the antimitotic toxin monomethyl auristatin E (MMAE).
BT8009 showed significant antitumor activity in preclinical tumor models for multiple cancer indications and was well tolerated in preclinical safety studies. It showed antitumor activity superior or equivalent to Padcev (enfortumab vedotin, EV) analogs in several models.
Figure 5. BT8009 structure, sourceL Bicycle official website 
BTCs are very similar to ADCs, except that the targeted molecules change from monoclonal antibodies to bicyclic peptides. Compared to ADCs, BTCs offer the advantages of potent tumor penetration, lower immunogenicity, and lower production costs.
Despite Padcev, an ADC targeting Nectin-4, has been granted accelerated approval in 2019 in the U.S., there are fewer ADC products laid out for the Nectin-4 target compared to popular targets such as HER2 and Trop2. In addition to monotherapy, the combination regimen of Nectin-4 ADCs with immune checkpoint inhibitors has also demonstrated excellent clinical potential. In addition, apart from uroepithelial cancer, Nectin-4 ADC is expected to further expand its indications to breast cancer, pancreatic cancer and ovarian cancer in the future.
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