doi: 10.1016/j.heliyon.2022.e10581. At present, ADC is an excellent and speedily growing field of targeted therapy for cancer, which combines the ability of monoclonal antibodies to specifically target oncology with a strong effect on killing activity. Preclinical safety profile of disitamab vedotina novel anti-HER2 antibody conjugated with MMAE. 2021. Emerging Targeted Therapies for HER2-Positive Breast Cancer. 1, 2 As monotherapy, disitamab vedotin has demonstrated antitumor activity in clinical trials in several solid t. In the same year, RemeGen announced FDAs clearance of an Investigational New Drug (IND) application for a Phase II clinical trial in mUC. The .gov means its official.Federal government websites often end in .gov or .mil. RT @FabioSchutz78: Ph1/2 trial with disitamab vedotin (ADC anti-HER2) + toripalimab in mUC. YANTAI, China, Sept. 25, 2020 /PRNewswire/ --RemeGen Co., Ltd. ("RemeGen") today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for disitamab vedotin (RC48), a novel humanized anti-HER2 antibody drug conjugate (ADC), for the second-line treatment of patients withHER2 positive locally advanced or metastatic urothelial cancer (UC) who have also previously received platinum-containing chemotherapy treatment. In addition, besides pinocytosis, clathrin-mediated and caveolin-mediated endocytosis were additional uptake pathways for naked antibodies and RC48, as it has been observed for the uptake of trastuzumab (Buckel etal., 2015). It shows that MMAEconjugated trastuzumab can not only remarkably enhance the cytotoxicity of trastuzumab, but also display the advantages of high affinity, specificity, and anti-tumor activity in HER2+ tumor cells. Seagen Inc. (Nasdaq: SGEN), a world leader and pioneer in antibody-drug conjugate (ADC) therapies, and RemeGen Co., Ltd. (9995.HK), a leading innovative biopharmaceutical company in China, today announced that the two companies have entered into an exclusive worldwide licensing agreement to develop and commercialize disitamab vedotin, a novel HER2-targeted ADC. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase i inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1, Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study, Antibody-Drug Conjugates in Breast Cancer: a Comprehensive Review. Furthermore, among the eligible patients included in this study, those who had not received prior treatment with HER2-targeted therapy and those who had previously accepted HER2-targeted therapy had ORR of 25.9% and 15.0%, respectively, and DCR of 48.1% and 45.0%, respectively (Xu etal., 2021). By providing your email address below, you are providing consent to Seagen to send you the requested Investor Email Alert updates. Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours. (202) 957 7795 Disitamab vedotin (RC48) is an investigational anti-HER2 antibody-drug conjugate targeting prevalent cancers with significant unmet medical needs and is the first domestically developed ADC to. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. (2015). RemeGen Co., Ltd. issued the following announcement on September 25. RemeGen. (2020b). Since its inception in 2008, RemeGen has created more than 10 novel drug molecules that are in various stages of development. Cytotoxin: Cytotoxin was also changed from dentin analog to MMAE, MMAE is a derivative of auristatin, which blocks cell cycle arrest through the aggregation of tissue microtubules bound to microtubules. from 8 AM - 9 PM ET. RemeGens main focus is research and development, manufacturing and commercialization of novel biologics, most notably monoclonal antibodies (mAb) and antibody-drug conjugates (ADCs). 2023 Mar 26;15(7):1987. doi: 10.3390/cancers15071987. https://www.businesswire.com/news/home/20210809005208/en/, Seagen Contacts: Drugs. A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer. Besides, the cytotoxic drug has a strong effect on the destruction of tumor cells, and it will also significantly affect every dividing cell, containing those in the normal tissues, resulting in serious adverse reactions (Wolska-Washer & Robak, 2019). Vice President, Media , . These derivatives comprise antibodies (disitamab) and cytotoxic drugs (monomethyl auristatin E, MMAE) linked by valine-citrulline (VC). (2019). View source version on businesswire.com: (2014). HER2 plays essential roles in the pathogenesis of multifarious oncology, such as BC, GC, UC, and NSCLC, making them distinguished candidate targets for novel therapies. T-DM1 has been approved for the treatment of previously treated HER2-positive metastatic breast cancer. Furthermore, it demonstrated that the cancer suppression dose of hertuzumab-VC-MMAE was significantly better than T-DM1, and the former was almost three times that of the latter; research on drug concentrations of total RC48-ADC and released MMAE in cancer tissues and serum showed that the RC48-ADC was targeting HER2 and released MMAE at the cancer site to maintain a steady concentration level for one week in HER2+ ovarian cancer models (Jiang etal., 2016). RC48 was the first ADC drug approved for human clinical trials in China and favorable safety profile has been observed in clinical trials. In addition, the company is conducting phase Ib and Phase II/III registered clinical trials of RC48 in metastatic breast cancer in China. Shitara K, Iwata H, Takahashi S, et al. (2017). Disitamab vedotin as monotherapy or combination therapy is also in clinical development for the treatment of other solid tumours globally, including urothelial cancer in China and the USA, and biliary tract cancer, non-small cell lung cancer and HER2-positive and HER2-low expressing breast cancer in China. (2017). (2020). Therefore, RC-48 with DAR 4 is optimal, and the half time (t1/2) and definite results of the PK characteristic of RC48 in rats were DAR-dependent (Jiang etal., 2016). View full prescribing information for Tivdak. Thirdly, specific PK and PD research should be executed on RC48 for the bystander effect and other profiles, while identifying predictive biomarkers and providing mechanistic insights to support clinical decision making. Seagen is a well-known global biotechnology company recognized for its capabilities in the field of oncology and ADC therapies. Would you like email updates of new search results? Peggy Pinkston Disitamab vedotin (Aidixi ) 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. Disitamab vedotin is being developed by RemeGen for the treatment of solid tumours, including gastric cancer. The analysis of population PK demonstrated that the distribution volume of MMAE in peripheral compartments was significantly higher than that in the central ventricle(29.0 and 59.3L, respectively) (Deeks, 2021). HHS Vulnerability Disclosure, Help PD1 combo solid tumor basket study is ongoing in HER2 1+expressing patients in China (breast, gastric, urothelial). Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. Santaniello G, Nebbioso A, Altucci L, Conte M. Mar Drugs. Do you want to continue to the external site and leave Seagen.com? 2023 Jan 24;15(3):713. doi: 10.3390/cancers15030713. (2011). MMAE was concentrated in tumor tissues, perhaps because after reaching the target site, RC48 was degraded into a toxin, which was then released, and as more antibodies entered the target site and MMAE continued to be released, MMAE accumulated in the tumor tissues, thereby resulting in high, tumor-specific cytotoxicity. About RC48RC48 was developed to treat HER2 expressing solid tumors. From our perspective, the toxicity of ADCs seems to be related to the stability of the conjugate in the bloodstream and the off-target effects of the payload. Available at https://www.nature.com/articles/s41598-018-19199-z.pdf?origin=ppub. -. 2020 May 15;324:30-37. doi: 10.1016/j.toxlet.2019.12.027. Disitamab vedotin (Aidixi ) 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. Disitamab vedotin is being developed by RemeGen for the treatment of solid tumours, including gastric cancer; Seagen . For information on the COVID-19 pandemic, see the following resources: Follow the Oncology Center of Excellence on Twitter @FDAOncology. RC48, shown in Figure 2, is spanned into three components: antibody, payload, and linker. jason.li@remegen.cn. This Breakthrough Therapy designation will bring RemeGen one step closer to finding a safe and effective treatment for this devastating disease. Very promising ORR of 73.2%, and responses observed irrespective of HER2 expression. This project was supported by the National Natural Science Foundation of China (31971248) and the Shaanxi Science and Technology Innovation Team Project (2021TD-46. Conjugating MMAE to a novel anti-HER2 antibody for selective targeted delivery. Cytotoxic payloads should have the following characteristics: firstly, which should be properly fat-soluble; secondly, the target should be located inside the cell; thirdly, cytotoxic payloads should be stable in the blood; last but not least, the cytotoxic payload molecules include the following characteristics: small dimensions, lack of immunogenicity, easy to dissolve in aqueous solution so that it is conducive to their combination. In July 2021, the NMPA accepted the New Drug Application for disitamab vedotin in locally advanced or . Despite this, no HER2-directed therapies are currently approved for UC. ADC: antibody-drug conjugates; DAR: drug/antibody ratio; SMCC: a non-cleavable small maleimidomethyl cyclohexane-1-carboxylate; BC-GGFG-OH: tert-butoxycarbonyl -glycyl glycyl phenylalanyl Glycine; MC-VC-PAB is a cathepsin cleavable ADC linker. FDA History Tivdak Print Save Tivdak FDA Approval History Last updated by Judith Stewart, BPharm on Sep 21, 2021. Bethesda, MD 20894, Web Policies Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Patients received tisotumab vedotin-tftv 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The anticancer mechanism of RC48. In June, RemeGen received conditional approval in China for disitamab vedotin as a treatment for HER2-expressing locally advanced or metastatic gastric cancer patients who have received two lines of prior chemotherapy. Currently, cytotoxic drug effector molecules contain microtubule inhibitors, DNA damaging agents, and DNA transcription inhibitors. By signing up you agree to receive content from us. Disitamab vedotin is conditionally approved for treating locally advanced metastatic gastric cancer in China, and in July 2021 the National Medical Products Administration (NMPA) of China also accepted a New Drug Application for disitamab vedotin in mUC. Firstly, the structure design of RC-48 has the advantage of improving the efficacy and ensuring safety, such as in terms of molecular construction, DS-8201 uses topoisomerase, which has a quick effect but large side effects, while RC-48 has low side effects and better safety. Tumor cells within the same carcinoma can exhibit different phenotypes and morphological characteristics, such as gene expression level, metabolism, cellular morphology, and motility as well metastatic potential (Swanton, 2012; O'Connor etal., 2015). Disitamab vedotin (RemeGen) is another anti-HER2 ADC in phase III development for breast cancer in China; . We look forward to working with the FDA to advance the clinical development of disitamab vedotin. Disitamab vedotin (RC48) is an innovative anti-HER2 ADC, including hertuzumab (a novel anti-HER2 mAB) coupling monomethyl auristatin E (MMAE) by a cleavable linker. 2018. A survival guide to HER2 testing in gastric/gastroesophageal junction carcinoma, Intratumor heterogeneity: evolution through space and time. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. Since its inception in 2008, RemeGen has createdmore than 10 novel drug moleculesthat are in various stages of development. The antibody part was a humanized monoclonal antibody targeting HER2, the small molecule toxin was monomethyl auristatin E (MMAE), a synthetic antineoplastic agent. 2019. The most familiar connectives are the following two: cleavable linker and uncleanable linker. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastrooesophageal junction adenocarcinoma (GAT SBY): an international randomised, open-label, adaptive, phase 2/3 study. . Products: product pipeline. Unable to load your collection due to an error, Unable to load your delegates due to an error. RemeGen Co., Ltd. disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. Disitamab vedotin (Aidixi) is an antibody-drug conjugate comprising a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) conjugated via a cleavable linker to the. As is well known that HER-2 status determines GC/GEJC that benefit from targeted therapy, HER2+ carcinoma is supposed to have invasive biologic behavior (Subasinghe etal., 2019). The role of Her2 and other oncogenes of the PI3K/AKT pathway in mitochondria. Disitamab vedotin (RC48), a novel ADC targeting human epidermal growth factor receptor 2 (HER2), is currently being explored in a variety of malignancies. The vein has been exploited during . The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 2020. For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCEs Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov. It is currently being studied in multiple late-stage clinical trials across solid tumor types. In 2021, ASCO announced the latest data of 70 patients with HER2+ BC and 48 patients with HER2-low expression BC, the trial results show that RC48 can achieve good efficacy in both HER2+ and low-expression BC patients, and there are no new safety problems, while the 2.0mg/Kg dose group had the best benefit-to-risk ratio, with m-PFS of 6.3months.

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