Abstract P5-08-02: MORAb-202, an antibody-drug-conjugate (ADC) targeting folate receptor alpha (FRα), exhibits durable anti-tumor efficacy in PDx models of TNBC
Authors: Keiji Furuuchi, Katherine Rybinski, James Fulmer, Tomoyuki Moriyama, Brian Drozdowski, Allis Soto, Shawn Fernando, Kerrianne Wilson, Andrew Milinichik, Mary Lou Dula, Keigo Tanaka, Xin Cheng, Earl Albone, Toshimitsu Uenaka
Journal: Cancer Research (2022)

Abstract Background MORAb-202 is an ADC consisting of a FRα-targeting antibody (farletuzumab) paired with a cathepsin B-cleavable linker and an eribulin payload. FRα is overexpressed in various solid tumors including TNBC where 30-40% are enriched for FRα expression. MORAb-202 is currently in phase 1 clinical trials in patients with advanced solid tumors expressing FRα including ovarian cancer, endometrial cancer, TNBC and NSCLC. Methods In vitro characterization of MORAb-202 was conducted against over 60 various cancer cell lines expressing various level of FRα. In vitro co-culture system was also developed to evaluate bystander effect of MORAb-202. The anti-tumor activity of MORAb-202 at single dose (5 mg/kg) by comparison with eribulin (3.2 mg/kg as 32x molarity of eribulin in MORAb-202 at 5 mg/kg) was evaluated in TNBC PDx models established from primary and metastatic tumors, with different levels of FRα expression. Target engagement and bystander effect of MORAb-202 in the tumor microenvironment (TME) were also evaluated by IHC/IF methods. Dose dependent anti-tumor activity and the PK/PD profile of the single administration of MORAb-202 were examined in a human cancer CDx model (NCI-H2110). Soluble FRα (sFRα) is one of PD biomarker candidates measured in this model. The toxicology study of MORAb-202 was conducted in cynomolgus monkey. Results MORAb-202 showed cytotoxicity to FRα-positive cells in vitro, with limited off-target killing of FRα-negative cells. There was linear correlation observed between IC50 of MORAb-202 and MFI of FRα, while no relationship between IC50 of eribulin and MFI of FRα. More importantly, MORAb-202 showed 100x potent in vitro bystander cytotoxic effect in co-culture with FRα-positive/negative cells. Next, In vivo antitumor efficacy studies of MORAb-202 in TNBC PDx models exhibited durable activity proportional to tumor FRα expression. Single treatment of MORAb-202 showed long-lasting anti-tumor activity on TNBC PDx models superior to a group treated with eribulin. No body weight loss was observed in a group of MORAb-202, while transient body weight loss (~10%) was observed in the eribulin group. IHC/IF studies in tumors collected post treatment of MORAb-202 revealed that target engagement of MORAb-202 and its bystander effect on the TME could account for the anti-tumor activity in the models. PK/PD &amp; anti-tumor activity of single administration of MORAb-202 (5 dose levels) were examined in human cancer CDx models (NCI-H2110). PK profiles of intact and total MORAb-202 were comparable. PD profile were assessed using sFRα, a potential biomarker candidate for clinic. In this model, spike of the sFRα was observed at 1 to 2 days post MORAb-202 treatment and returned to baseline levels by Day 4 post treatment. In cynomolgus monkeys, the AUC after the 2nd treatment of MORAb-202 on Day 22 was almost similar with that after the 1st treatment on Day 1. Elimination half-life T1/2 of MORAb-202 in plasma was nearly 5 days, supporting Q3W schedule in human clinical trials. The major toxicity observed with MORAb-202 treatment was hematologic toxicity. Conclusion These findings suggest MORAb-202 may be a promising ADC for TNBC and warrants further clinical investigation in this setting. Citation Format: Keiji Furuuchi, Katherine Rybinski, James Fulmer, Tomoyuki Moriyama, Brian Drozdowski, Allis Soto, Shawn Fernando, Kerrianne Wilson, Andrew Milinichik, Mary Lou Dula, Keigo Tanaka, Xin Cheng, Earl Albone, Toshimitsu Uenaka. MORAb-202, an antibody-drug-conjugate (ADC) targeting folate receptor alpha (FRα), exhibits durable anti-tumor efficacy in PDx models of TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-02.