Mirvetuximab soravtansine, also known as IMGN853, is a FRα-targeting antibody-drug conjugate or ADC being developed and wholly owned by ImmunoGen. The trial drug is the first and only ADC to this target to enter clinical testing, and comprises a folate receptor α (FRα)-binding antibody conjugated, via the hindered disulfide sulfo-SPDB linker, to the maytansinoid DM4, a potent cancer-cell killing agent developed by ImmunoGen specifically for use in ADCs. The antibody serves to target the highly potent maytansinoid DM4 specifically to the folate receptor α (FRα)-positive cancer cells. The maytansinoid DM4 induces cell-cycle arrest and cell death by targeting microtubules.
According to published peer reviewed data, expression of folate receptor α (FRα) in normal human tissues is restricted to the kidney proximal tubule, lung, choroid plexus, thyroid, ovary, fallopian tubes, placenta, esophagus, stomach, pancreas, salivary gland, and mammary gland.
In tumors, the folate receptor α (FRα) is highly expressed on many cases of epithelial ovarian cancer, and on other types of solid tumors including endometrial cancer and some non-small cell lung cancers. Therefore, mirvetuximab soravtansine is being assessed for the treatment of FRα-positive, platinum-resistant ovarian cancer and for FRα-positive relapsed and/or refractory endometrial cancer, with additional assessments anticipated.
Mirvetuximab soravtansine consists of the maytansinoid DM4 (N2′- Deacetyl-N2′-(4-mercapto-4-methyl-1-oxopentyl)-maytansine conjugated to the M9346A anti- FRα antibody via the N-Succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate linker (Sulfo-SPDB). Maytansinoids are anti-mitotic agents that inhibit tubulin polymerization and microtubule assembly. In mirvetuximab soravtansine, each antibody molecule is conjugated to an average of 3-4 molecules of maytansinoid DM4.
In efficacy studies of mirvetuximab soravtansine in xenografts of ovarian cancer and non-small cell lung cancer cell lines and of a patient tumor-derived xenograft model demonstrated that the trial drug was highly active against tumors that expressed FRα at levels similar to those found on a large fraction of ovarian and non-small cell lung cancer patient tumors, as assessed by immunohistochemistry. Mirvetuximab soravtansine displayed cytotoxic activity against FRα-negative cells situated near FRα-positive cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FRα.
Mirvetuximab soravtansine is currently being assessed in the Phase II FORWARD I trial as a single-agent therapy for patients with FRα-positive ovarian cancer that has been treated with 3-4 prior regimens. The drug is also being assessed in combination regimens for patients with FRα-positive ovarian cancer in the Phase Ib/II FORWARD II trial. 
Orphan Drug designation
The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to mirvetuximab soravtansine for the treatment of ovarian cancer. The trial drug has also received this designation in the European Union.
In general, orphan drugs follow the same regulatory development path as any other pharmaceutical product, focuses on pharmacokinetics and pharmacodynamics, dosing, stability, safety and efficacy. However, to maintain development momentum, a number of statistical burdens are lessened. For example, because the orphan drugs are targeting rare diseases or diseases affecting smaler number of patients, orphan drug regulations acknowledge that it may not be possible to test 1,000 patients in a phase III clinical trial.
In March 2022 Immunogen submitted a Biologics License Application (BLA) under the accelerated approval pathway to the US Food and Drug Administration (FDA) for mirvetuximab soravtansine monotherapy in patients with folate receptor alpha (FRα)-high platinum-resistant ovarian cancer who have been previously treated with 1 to 3 prior systemic treatments. The BLA submission was based on results from the pivotal Phase 3 SORAYA trial presented at the Society of Gynecologic Oncology (SGO) 2022 Annual Meeting in Phoenix, AZ.
A Study of Mirvetuximab Soravtansine in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (SORAYA) – NCT04296890
A Study of Mirvetuximab Soravtansine vs. Investigator’s Choice of Chemotherapy in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (MIRASOL) –NCT04209855
Mirvetuximab Soravtansine Monotherapy in Platinum-Sensitive Epithelial, Peritoneal, and Fallopian Tube Cancers (PICCOLO) – NCT05041257
 Weitman SD, Lark RH, Coney LR, et al. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Research 52: 3396-3401, 1992.
 Parker N, Turk MJ, Westrick E, Lewis JD, Low PS, Leamon CP. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem. 2005 Mar 15;338(2):284-93.
 Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, LaBelle A et al. IMGN853, a folate receptor-α (FRα)-targeting antibody-drug conjugate, exhibits potent targeted antitumor activity against FRα- expressing tumors. Molecular Cancer Therapeutics 14(7): 1605-1613, 2015.
 Study of IMGN853 in Comb. With Bevacizumab, Carboplatin or PLD in Adults With FRa + Adv. EOC, Primary Peritoneal, Fallopian Tube, or Endometrial Cancer – NCT02606305
 PH2 Study of IMGN853 vs Investigator’s Choice of Chemo in Adults With FRa+ Adv. EOC, Primary Peritoneal or Primary Fallopian Tube Cancer – NCT02631876
 Designating an Orphan Product: Drugs and Biological Products; U.S. Food and Drug Administration. Website. Last accessed March 17, 2016.