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

Abstract

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. Semi-quantitative IHC analysis indicated that 41% of the USC patients overexpress FRα. Further, overexpression of FRα (ie, 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 to 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< 0.001). Treatment with IMGN853 in USC PDX model (BIO(K)1), expressing 2+ FRα, induced 2-fold increase in median survival (p< 0.001). IMGN853 shows impressive anti-tumor activity in biologically aggressive FRα 2+ uterine cancers. This preclinical data suggests that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FRα may benefit from this treatment.

Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer

“…Survival curves were compared using the log-rank test. A two-sided p < 0.05 was considered to be significant (7).…”

“…A retrospective, stage I-IV ovarian cancer cohort [EOC N = 90 formalin-fixed-paraffin-embedded (FFPE) tumors] represented in tissue microarray (TMA) format was used to evaluate TROP-2 expression by immunohistochemistry (IHC). Briefly, as described in previous studies (7), representative areas of primary high-grade serous carcinomas ovarian cancers, in hematoxylin/eosin-stained preparations and 0.6 mm cores were obtained and arrayed in a recipient block. From different areas of each tumor, four different cores were selected and included in the TMAs, to maximize tumor representation and capture possible marker heterogeneity.…”

“…Briefly, a Trop-2 negative uterine serous cell line (i.e., ARK4) stably transfected with a Green Fluorescence Protein (GFP) plasmid (pCDH-CMV-MCSEF1-copGFP, a gift from Dr. Simona Colla, MDACC) (7), was plated alone (80,000 cells/well) or mixed with KRCH31 (3+ Trop-2 expressing EOC cell line) (40,000 ARK4 cells/well and 20,000 KRCH31) in 6-well plates (2 mL/well). After overnight incubation, cells were treated with 1 nM of SG or control ADC (h679-CL2A-SN-38) for 12 h, as described above.…”

“…ADC may optimize tumor targeting in vivo while potentially minimizing the side effects of highly toxic chemotherapy agents (4,5). One of the main challenges in ADC development is the generation of linkers able to maintain the integrity of ADC in human system and allowing the release of the toxic payload after internalization or in close proximity, of the targetcells (5)(6)(7).…”

Sacituzumab govitecan, an antibody‐drug conjugate targeting trophoblast cell‐surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo

“…For example, T‐DM1 (Kadcyla; Genentech/Roche, South San Francisco, CA, USA) is currently approved by the European Medical Agency (EMA) and FDA for patients with HER2‐positive metastatic breast cancer. Additionally, IMGN853 (Immunogen, Waltham, MA, USA) has already demonstrated high preclinical activity against type II endometrial cancer and other solid tumors (Ab et al , ; Altwerger et al , ; English et al , ; Nicoletti et al , ).…”