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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The experimental ADC mirvetuximab soravtansine (IMGN853) is an example of a DM4-based conjugate, with the INN name soravtansine representing a combination of DM4 and ImmunoGen’s sSPDB linker. In 2018, the FDA granted fast track designation to this ADC for the treatment of patients with medium to high FRα-positive platinum-resistant ovarian cancer.
Antibody-drug conjugates: Design and development for therapy and imaging in and beyond cancer, LabEx MAbImprove industrial workshop, July 27–28, 2017, Tours, France
Published in mAbs, 2018
Camille Martin, Claire Kizlik-Masson, André Pèlegrin, Hervé Watier, Marie-Claude Viaud-Massuard, Nicolas Joubert
The first session dealt with the challenge of improving cancer therapy using ADCs and gave a comprehensive overview of the field. It was chaired by Dr. Nicolas Joubert (GICC CNRS UMR 7292, Labex MabImprove, University of Tours, Tours, France) and started with a talk from Dr. Ravi Chari (ImmunoGen, Waltham, USA). He introduced the aim that has driven ADC research for decades: improving the therapeutic index by lowering the minimum effective dose and increasing the maximum tolerated dose. He described the development of the first ADC against solid tumors, Kadcyla®, an anti- human epidermal growth factor receptor-2 (HER2) ADC with a maytansinoid payload, underlining the process of drug and linker selection. Many challenges must be overcome for a payload to be suitable for use in an ADC: aqueous solubility, stability in blood stream, amenability to chemical modifications, and high potency; criteria that were met by maytansine. Several in vitro and in vivo studies were presented, highlighting the differences of activity in vivo of three different disulfide linkers with varying cleavage rates, and a non-cleavable linker, depending on the model and target.2 There was a particular focus on the demonstration of a bystander killing effect for ADCs with cleavable linkers, leading to positive results on co-culture models mimicking heterogeneous tumors. Dr. Chari then introduced a new ADC, mirvetuximab soravtansine. This ADC, which targets folate receptor-α, uses a new linker with a sulfonic moiety to increase its hydrophilicity, and is linked to a maytansinoid payload.3 First trial results were very encouraging, with an objective response rate (ORR) of 47% and a median progression-free survival (PFS) of 6.7 months. Mirvetuximab soravtansine is now ongoing a Phase 3 study in platinum-resistant ovarian cancer.
Antibodies to watch in 2019
Published in mAbs, 2019
Hélène Kaplon, Janice M. Reichert
ADC ‘antibodies to watch’ include mirvetuximab soravtansine (ImmunoGen), trastuzumab duocarmazine (Synthon BioPharmaceuticals), and depatuxizumab mafodotin (Abbvie). Mirvetuximab soravtansine, an ADC that targets α-folate receptor 1, is undergoing evaluation in the Phase 3 FORWARD I study (NCT02631876) of patients with folate receptor alpha-positive advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer. This study has a primary completion date in November 2018, and top-line results from the study are expected in the first half of 2019. The safety and efficacy of anti-HER2 trastuzumab duocarmazine (Synthon BioPharmaceuticals) is being evaluated in the Phase 3 TULIP study (NCT03262935) of patients with human epidermal growth factor receptor 2 (HER2)-positive unresectable locally advanced or metastatic breast cancer. This study has a primary completion date in May 2019. Trastuzumab duocarmazine was granted a Fast Track designation for treating patients diagnosed with HER2-positive metastatic breast cancer that has progressed during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease, or progressed during or after [ado-]trastuzumab emtansine treatment. The anti-epidermal growth factor receptor ADC depatuxizumab mafodotin is being evaluated as a treatment for glioblastoma in two Phase 3 studies, NCT03419403 and NCT02573324, with primary completion dates in September 2019 and March 2020, respectively. In addition, anti-DLL3 rovalpituzumab tesirine (AbbVie) is undergoing evaluation in three Phase 3 studies of small cell lung cancer (SCLC) patients, TAHOE (NCT03061812), MERU (NCT03033511) and M16-292 (NCT03334487), with primary completion dates in September 2019, November 2019, and September 2020. However, AbbVie announced in March 2018 that they will not seek accelerated approval for rovalpituzumab tesirine in third-line relapsed/refractory SCLC based on the magnitude of effect across multiple parameters in the Phase 2 TRINITY study.93
Antibody therapeutics for epithelial ovarian cancer
Published in Expert Opinion on Biological Therapy, 2022
Mason Ruiz, Ningyan Zhang, Anil K Sood, Zhiqiang An
In a phase 3 clinical trial named SORAYA, a first in class ADC targeting FRɑ conjugated with the potent tubulin inhibitor maytansinoid DM4, named mirvetuximab soravtansine, has shown promising results in demonstrating clinically meaningful antitumor activity in FRɑ-high platinum-resistant ovarian cancer and had an objective response rate of 32.4% compared to non-platinum-based chemotherapies which have overall response rates of 4–13% and have significant toxicities [84]. The FDA granted mirvetuximab soravtansine fast track designation in 2018, and in March of 2022, based on the phase 3 SORAYA trial results, ImmunoGen, Inc. submitted a Biologics License Application (BLA) under the accelerated approval pathway in patients with FRɑ-high platinum-resistant ovarian cancer [85]. The BLA for mirvetuximab soravtansine was accepted with priority review by the FDA on 23 May 2022 and has a Prescription Drug User Fee Act (PDUFA) action date of 28 November 2022 [86]. Another antibody drug conjugate that is being evaluated for the treatment of ovarian cancer is upifitamab rilsodotin, which is a NaPi2b-directed ADC and has been granted fast track designation by the FDA. NaPi2b is a sodium-dependent phosphate transporter that is expressed by the gene SLC34A2 which is present in 80–90% of epithelial ovarian cancer, and plays an important role in maintaining human phosphate metabolism [87]. Upifitamab rilsodotin has shown favorable safety and efficacy profiles in a phase 1 study and is undergoing further evaluation [88]. The level of NaPi2b expression in tumors appears to be critical, as seen in a study evaluating an anti-NaPi2b ADC in non-small cell lung (NSCLC) and ovarian cancer, which furthered the hypothesis that NaPi2b target expression is necessary for clinical benefit, showing that objective responses only occurred in patients with high tumor NaPi2B expression [89]. Furthermore, the upregulation of SLC34A2 has the potential to serve as a prognostic biomarker in brain, ovarian, and pancreatic cancers [90]. Targets such as mesothelin, FRα, the tissue factor-fVII complex and TROP2 are also currently being targeted with ADCs [91–94].