In Vitro and In Vivo Activity of IMGN853, an Antibody–Drug Conjugate Targeting Folate Receptor Alpha Linked to DM4, in Biologically Aggressive Endometrial Cancers

Published on May 1, 2018in Molecular Cancer Therapeutics5.615
· DOI :10.1158/1535-7163.MCT-17-0930
Gary Altwerger12
Estimated H-index: 12
(Yale University),
Elena Bonazzoli16
Estimated H-index: 16
(Yale University)
+ 22 AuthorsAlessandro D. Santin62
Estimated H-index: 62
(Yale University)
Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FRα) expression in these biologically aggressive (type II) endometrial cancers and evaluate FRα as a targetable receptor for IMGN853 (mirvetuximab soravtansine). The expression of FRα was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FRα. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/patient-derived xenograft (PDX) models. Semiquantitative IHC analysis indicated that 41% of the USC patients overexpress FRα. Further, overexpression of FRα (i.e., 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared with control in 2+ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FRα showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FRα = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FRα, IMGN853 treatment showed complete resolution of tumors ( P P Mol Cancer Ther; 17(5); 1003–11. ©2018 AACR .
📖 Papers frequently viewed together
29 Citations
30 Citations
6 Citations
#1Kathleen N. Moore (University of Oklahoma Health Sciences Center)H-Index: 44
#2Hossein Borghaei (Fox Chase Cancer Center)H-Index: 49
Last. Michael J. BirrerH-Index: 109
view all 13 authors...
BACKGROUND Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors. METHODS Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose...
31 CitationsSource
#1William T. Creasman (MUSC: Medical University of South Carolina)H-Index: 61
#2Shamshad Ali (Roswell Park Cancer Institute)H-Index: 17
Last. David Miller (UTSW: University of Texas Southwestern Medical Center)H-Index: 88
view all 18 authors...
Abstract Objective To report clinical and pathologic relationships with disease spread in endometrial cancer patients. Methods Surgical candidates with uterine cancer (adenocarcinoma or carcinosarcoma) who were eligible to participate in a surgical pathological study to create a clinically annotated tissue biorepository to support translational and clinical research studies. All patients were to undergo a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphad...
28 CitationsSource
#1Kathleen N. Moore (University of Oklahoma Health Sciences Center)H-Index: 44
#2Lainie P. Martin (Fox Chase Cancer Center)H-Index: 28
Last. Michael J. Birrer (Sarah Cannon Research Institute)H-Index: 109
view all 9 authors...
PurposeThis phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody–drug conjugate consisting of a humanized anti–folate receptor alpha (FRα) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRα-positive and platinum-resistant ovarian cancer.Patients and MethodsPatients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN85...
71 CitationsSource
#1Peter G. Rose (Cleveland Clinic)H-Index: 33
#2Shamshad Ali (Roswell Park Cancer Institute)H-Index: 17
Last. Fiona Simpkins (UPenn: University of Pennsylvania)H-Index: 26
view all 4 authors...
ObjectiveThe aim of this study was to evaluate the efficacy of adding bevacizumab to paclitaxel and carboplatin and as maintenance in a larger cohort of patients with advanced or recurrent endometrial carcinoma.MethodsWe retrospectively identified endometrial cancer patients treated with paclitaxel
10 CitationsSource
#1Jose F. Ponte (ImmunoGen, Inc.)H-Index: 10
#2Olga Ab (ImmunoGen, Inc.)H-Index: 10
Last. Rodrigo Ruiz-Soto (ImmunoGen, Inc.)H-Index: 7
view all 10 authors...
Abstract Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved ther...
29 CitationsSource
#1Kimberly D. Miller (ACS: American Cancer Society)H-Index: 28
#2Rebecca L. Siegel (ACS: American Cancer Society)H-Index: 67
Last. Ahmedin Jemal (ACS: American Cancer Society)H-Index: 139
view all 9 authors...
The number of cancer survivors continues to increase because of both advances in early detection and treatment and the aging and growth of the population. For the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborate to estimate the number of current and future cancer survivors using data from the Surveillance, Epidemiology, and End Results cancer registries. In addition, current treatment patterns for the most prevalen...
3,824 CitationsSource
#1Rebecca L. Siegel (ACS: American Cancer Society)H-Index: 67
#2Kimberly D. Miller (ACS: American Cancer Society)H-Index: 28
Last. Ahmedin Jemal (ACS: American Cancer Society)H-Index: 139
view all 3 authors...
Abstract Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Can...
10.8k CitationsSource
#1J. A. LedermannH-Index: 1
#2Silvana CanevariH-Index: 65
Last. Tate Thigpen (University of Mississippi)H-Index: 20
view all 3 authors...
Abstract Background In cancer therapy, molecularly targeted agents have the potential to maximize antitumor efficacy while minimizing treatment-related toxicity. However, these agents may only be effective in specific tumor subtypes with defined genomic profiles. This emphasizes the importance of developing personalized cancer therapeutic strategies (i.e. through the use of companion diagnostic tests) to appropriately select and treat patients who are likely to benefit from specific targeted the...
126 CitationsSource
#1Serkan Senol (Istanbul Medeniyet University)H-Index: 6
#2Ayse Bahar Ceyran (Istanbul Medeniyet University)H-Index: 4
Last. Ibrahim Akalin (Istanbul Medeniyet University)H-Index: 7
view all 8 authors...
Endometrioid-type endometrial carcinoma (EEC) developing on the ground of endometrial hyperplasia (EH) is amongst the most commonly observed type of cancer in the world. Folate receptor α (FRα) is a vitamin molecule that has a role in cell proliferation. The fact that FRα, which is known to be needed extremely by the cells of malignancies that proliferate rapidly, is present in limited amounts in normal tissues while it is overexpressed in malignant cells of the same tissues makes folate a candi...
16 Citations
#1Olga Ab (ImmunoGen, Inc.)H-Index: 10
#2Kathleen R. Whiteman (ImmunoGen, Inc.)H-Index: 13
Last. John M. Lambert (ImmunoGen, Inc.)H-Index: 52
view all 13 authors...
A majority of ovarian and non–small cell lung adenocarcinoma cancers overexpress folate receptor α (FRα). Here, we report the development of an anti-FRα antibody–drug conjugate (ADC), consisting of a FRα-binding antibody attached to a highly potent maytansinoid that induces cell-cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FRα monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoi...
79 CitationsSource
Cited By9
#1Joan Tymon-Rosario (Yale University)H-Index: 6
#2Burak ZeybekH-Index: 14
Last. Alessandro D. SantinH-Index: 62
view all 3 authors...
PURPOSE OF REVIEW Antibody-drug conjugates (ADCs) represent a new class of drugs that combine a surface receptor-targeting antibody linked to a cytotoxic molecule. This review summarizes the current literature demonstrating their tremendous promise as therapeutic agents in the treatment of aggressive gynecologic malignancies. RECENT FINDINGS Several antigens have proven to be differentially overexpressed in a variety of gynecologic tumors when compared with normal surrounding tissue and serve as...
#1Emanuele Perrone (Yale University)H-Index: 12
#2Paola Manara (Yale University)H-Index: 8
Last. Alessandro D. Santin (Yale University)H-Index: 62
view all 22 authors...
Endometrial cancer is the most common gynecologic malignancy in developed countries. The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) targets trophoblast cell-surface antigen-2 (Trop-2) - a cell-surface glycoprotein highly expressed in many epithelial tumors - and delivers the active metabolite of irinotecan SN-38 to Trop-2-positive tumor cells. We evaluated Trop-2 expression in endometrial endometrioid carcinoma (EC) tissues and the activity of SG against primary poorly differentiat...
6 CitationsSource
#1Emanuele Perrone (Yale University)H-Index: 1
#1Emanuele Perrone (Yale University)H-Index: 12
Last. Alessandro D. Santin (Yale University)H-Index: 62
view all 22 authors...
Background Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods Trop-2 expression was ass...
5 CitationsSource
#1Donmienne Doen Mun Leung (Eli Lilly and Company)H-Index: 7
#2Jacqueline M Wurst (Eli Lilly and Company)H-Index: 1
Last. Yiqing Feng (Eli Lilly and Company)H-Index: 2
view all 6 authors...
Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein therapeutics cannot drug targets intracellularly and are limited to soluble and cell-surface antigens. Tremendous strides have been made in antibody discovery, protein engineering, fo...
17 CitationsSource
#1Sachiko Shiba (Saitama Medical University)H-Index: 7
#2Kazuhiro Ikeda (Saitama Medical University)H-Index: 36
Last. Satoshi Inoue (Saitama Medical University)H-Index: 80
view all 8 authors...
: Low-grade and early-stage endometrial cancer usually has a favorable prognosis, whereas recurrent or metastatic disease is often difficult to cure. Thus, the molecular mechanisms underlying advanced pathophysiology remain to be elucidated. From the perspective of the origin of advanced endometrial cancer, the characterization of cancer stem-like cells (CSCs) will be the first step toward the development of clinical management. We established long-term culturable patient-derived cancer cells (P...
6 CitationsSource
#1Tetsuya Kokabu (Kyoto Prefectural University of Medicine)H-Index: 5
#2Taisuke Mori (Kyoto Prefectural University of Medicine)H-Index: 14
Last. Jo Kitawaki (Kyoto Prefectural University of Medicine)H-Index: 27
view all 7 authors...
Purpose The estrogen-related receptor (ERR) α is structurally similar to classical estrogen receptors (ERs), but is considered to be an orphan nuclear receptor. We previously found that ERRα regulates uterine endometrial cancer progression. Here, we investigated the efficacy of XCT790, a selective inverse agonist of ERRα, on endometrial cancer cells in vitro and in vivo.
2 CitationsSource
#1Cong Ava Fan (UMB: University of Maryland, Baltimore)H-Index: 1
#2Jocelyn Reader (UMB: University of Maryland, Baltimore)H-Index: 12
Last. Dana M. Roque (UMB: University of Maryland, Baltimore)H-Index: 18
view all 3 authors...
The rise of immunotherapy is the greatest advance in oncology to occur over the last several years, but applications in gynecologic malignancies lag behind other tumors. The term “immunotherapy” envelops monoclonal antibodies as receptor mediators, including immune checkpoint inhibitors (ICPI), cancer vaccines, and adoptive immunotherapies alone or in combination with other therapeutic approaches. The purpose of this review is to summarize the status of immunotherapy trials in ovarian cancer and...
25 CitationsSource
#1Gianluca Lopez (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico)H-Index: 10
#2Francesca Boggio (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico)H-Index: 7
Last. Alessandro Del Gobbo (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico)H-Index: 10
view all 5 authors...
Despite the significant recent achievements in the diagnosis and treatment of colorectal cancer (CRC), the prognosis of these patients has currently plateaued. During the past few years, the opportunity to consider multiple treatment modalities (including surgery and other locoregional treatments, systemic therapy, and targeted therapy) led to the research of novel prognostic and predictive biomarkers in CRC liver metastases (CRCLM) patients. In this review, we seek to describe the current state...
5 CitationsSource