Abstract B115: MORAb-202: a folate receptor alpha (FRA)-targeting antibody-drug conjugate, exhibiting targeted antitumor activity and bystander elimination of cancer-associated fibroblasts
Authors: Rybinski Katherine A. , Maddage Christopher , Cheng Xin , Albone Earl , Grasso Luigi , Furuuchi Keiji , Uenaka Toshimitsu 
Published: August 2018

Triple-negative breast cancer (TNBC) is a highly metastatic disease with very poor long-term prognosis. Because of the lack of well-defined molecular targets, traditional chemotherapy is currently the only therapeutic regimen for TNBC. Within this agent class, eribulin has been approved for metastatic breast cancer and the prespecified subgroup analysis in phase 3 clinical trial (study301) revealed that eribulin demonstrated the greatest therapeutic benefit on overall survival of TNBC patients among all other breast cancer subtypes. Folate receptor alpha (FRA) is a GPI-linked membrane glycoprotein that has limited expression in normal tissue, but is highly overexpressed on a large number of cancers of epithelial origin, including non-small cell lung cancer (NSCLC), ovarian cancer, and TNBC. These features make FRA an attractive target for the treatment of TNBC using targeted therapeutic approaches. Farletuzumab, a humanized monoclonal antibody targeting FRA, has been investigated in multiple clinical trials enrolling patients overexpressing FRA. MORAb-202, a novel antibody-drug conjugate (ADC) consisting of farletuzumab conjugated to eribulin, targets FRA overexpressed by a variety of tumor types including TNBC. Upon binding and internalization, it is hypothesized that the liberated eribulin elicits both a direct cytotoxic effect on FRA-positive tumor cells and a bystander effect on FRA-negative tumor cells and, importantly, tumor-associated stromal cells within the tumor microenvironment. To address this hypothesis, we have evaluated the in vivo efficacy of MORAb-202 against a FRA-positive TNBC patient-derived xenograft (PDX) model. Single administration of 5 mg/kg MORAb-202 mediated tumor regression statistically compared to vehicle control (P&lt;0.0001). Additionally, one animal treated with MORAb-202 showed complete and durable tumor regression. In order to examine the effects of MORAb-202 treatment on the tumor microenvironment, we harvested tumors both prior to treatment and five days post-treatment. Immunofluorescent staining was used to assess the target-specific engagement of MORAb-202 to FRA-positive regions of the tumor. Strong membrane staining of MORAb-202 was observed, while no staining was seen in the adjacent stromal regions. MORAb-202 also had demonstrable effects on the tumor microenvironment via reduction of the number of FRA-negative cancer-associated fibroblasts (CAF) present. To further evaluate whether these effects on CAF are part of the mode of action (MOA) of MORAb-202, we tested the antitumor efficacy and effects on the tumor microenvironment in a surrogate FRA-positive in vivo model. Tumors were isolated on days 3, 5, 7, and 9 post-treatment. The reduction in CAF, visualized by alpha-smooth muscle actin staining, was directly proportional to overall tumor reduction. In both studies, single-dose MORAb-202 showed dramatically greater efficacy than molar equivalent dosing of eribulin alone. Histologic analyses revealed unique modes of action of MORAb-202 over antibody or payload alone. These results suggest a potential benefit of MORAb-202 in the treatment of TNBC.

Citation Format: Katherine A. Rybinski, Christopher Maddage, Xin Cheng, Earl Albone, Luigi Grasso, Keiji Furuuchi, Toshimitsu Uenaka. MORAb-202: a folate receptor alpha (FRA)-targeting antibody-drug conjugate, exhibiting targeted antitumor activity and bystander elimination of cancer-associated fibroblasts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B115.