Disitamab vedotin (brand name Aidixi in China, development code RC48) is an antibody-drug conjugate (ADC) developed by RemeGen for the treatment of various HER2-positive cancers. It comprises a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2) conjugated via a cleavable linker to the cytotoxic agent monomethyl auristatin E (MMAE).
Disitamab vedotin became the first homegrown ADC approved in China in 2021, initially for the treatment of HER2-overexpressing gastric cancer.
Structure and mechanism Disitamab vedotin is an antibody-drug conjugate comprising a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) conjugated via a cleavable linker to the cytotoxic agent monomethyl auristatin E (MMAE). The conjugation occurs through a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker, with an average of 4 cysteinyl residues conjugated to MMAE. The mechanism of action involves binding to HER2-positive tumor cells, followed by internalization and intracellular release of MMAE, which disrupts microtubule assembly and leads to cell death. Disitamab vedotin enhances antitumor immunity.
Clinical development Gastric cancer In June 2021, disitamab vedotin received its first Biologics License Application (BLA) approval in China for the treatment of patients with HER2-overexpressing (defined as IHC2+ or 3+) locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) who have received at least two prior systemic chemotherapy regimens.
Urothelial carcinoma Clinical studies in HER2-positive locally advanced or metastatic urothelial carcinoma have shown promising results. More than half of patients (50.5%) achieved objective response with the median progression-free survival (PFS) of 5.9 months and the median overall survival (OS) of 14.2 months with a well-tolerated safety profile.
Other malignancies Disitamab vedotin is being investigated for the treatment of various other HER2-expressing solid tumors, including: Breast cancer Bladder cancer Gynecological cancer
Regulatory status China In June 2021, the NMPA granted conditional approval of disitamab vedotin (Aidixi) for the treatment of patients with HER2-overexpressing locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) who have received at least two systemic chemotherapy regimens.
United States The U.S. Food and Drug Administration (FDA), in September 2021, granted Breakthrough Therapy designation for disitamab vedotin for the second-line treatment of patients with HER2 positive locally advanced or metastatic gastric cancer following treatment with platinum-based chemotherapy..
Combination therapy RC48 is a newly developed ADC drug targeting HER2 that comprises hertuzumab coupled with monomethyl auristatin E (MMAE) via a cleavable linker. Studies have investigated disitamab vedotin in combination with immune checkpoint inhibitors such as toripalimab for HER2-expressing advanced gastric or gastroesophageal junction and other solid tumors.
Real-world studies have also evaluated the combination of disitamab vedotin with immune checkpoint inhibitors for locally advanced bladder urothelial carcinoma.
Administration and dosing Disitamab vedotin is administered intravenously. The recommended dosing regimen varies based on the indication and has been established through dose-escalation studies in various cancer types.
Development and partnerships Disitamab vedotin is developed by RemeGen, a Chinese biotechnology company. The company has established partnerships for global development and commercialization, including collaborations with Pfizer.
See also Trastuzumab emtansine (T-DM1) Trastuzumab deruxtecan (T-DXd) Antibody-drug conjugate HER2-positive breast cancer Gastric cancer
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