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

Autor: 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
Rok vydání: 2022
Předmět:
Zdroj: Cancer Research. 82:P5-08
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.sabcs21-p5-08-02
Popis: 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 & 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.
Databáze: OpenAIRE
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