farletuzumab (MORAB-003)

A 2nd generation FOLR1-CAR T cell was created by fusing the ScFv from farletuzumab (anti-FOLR1 monoclonal antibody) with a 4-1BB costimulatory and CD3z cytotoxicity domain... FOLR1-CAR T cells appear to have in vivo activity against U2OS cell line and support further testing of safety and feasibility in an early phase clinical trial for relapsed/refractory OS. >

Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950).

The clinical development of antibody drug conjugates (ADCs) in ovarian cancer began in 2008 with farletuzumab, a humanized monoclonal antibody, and vintafolide, an antigen drug conjugate, both targeting alpha folate receptor...In September 2021, the FDA approved tisotumab vedotin (TV) in recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This was followed in November 2022, by the approval of mirvetuximab soravtansine (MIRV) for adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens...We also outline new concepts in the field of ADCs, including promising targets such as NaPi2 and novel drug delivery platforms such as dolaflexin with a scaffold-linker. Finally, we briefly present challenges in the clinical management of ADC toxicities and the emerging role of ADC combination therapies, including chemotherapy, anti-angiogenic and immunotherapeutic agents.

P3, N=1100, Terminated, Morphotek | Completed --> Terminated; Lack of efficacy

We generated a FOLR1-directed CAR using anti-FOLR1 binder (Farletuzumab), IgG4 intermediate spacer and 41-BB/CD3zeta signaling domains... We tested the target specificity of FOLR1-directed CAR T cells against FOLR1-positive (CBF/GLIS-CB, WSU-AML, Kasumi-1 FOLR1+ ) and FOLR1-negative (Kasumi-1) cells. CD8 FOLR1 CAR T cells demonstrated cytolytic activity against FOLR1 positive but not FOLR1 negative cells ( Figure 1B ). Furthermore, both CD8 and CD4 FOLR1 CAR T cells produced higher levels of IL-2, IFN-

Background MORAb-202 is an ADC consisting of a FRα-targeting antibody (farletuzumab) paired with a cathepsin B-cleavable linker and an eribulin payload. 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.

The ADC could be a more reasonable choice than mAb as a targeting agent for the FOLRα-expressing tumor.

The antibody-drug conjugate (ADC) MORAb-202, consisting of farletuzumab paired with a cathepsin B-cleavable linker and eribulin, targets folate receptor alpha (FRA), which is frequently overexpressed in various tumor types. Toxicology studies (Q3Wx2) in non-human primates suggested that the major observed toxicity of MORAb-202 is hematologic toxicity. Overall, these findings support the concept that MORAb-202 represents a promising investigational ADC for the treatment of TNBC patients.

The current investigation of intraperitoneal therapy with At-farletuzumab, delivered at clinically relevant At-mAb radioactivity concentrations and specific activities, showed a 6 to 10-fold increase (treated versus controls) in antitumor efficacy. This observation warrants further clinical testing.

Farletuzumab, an ADCC-activating, humanized antibody targeted against folate receptor alpha-1 (FOLR1), improves survival advantage for a very small subset of ovarian cancer patients having low cancer antigen-125 levels...In summary, the described BaCa antibody strategy represents a “moonshot strategy” to generate effective therapy for advanced-stage serous adenocarcinoma patients without the intervention of immune effector cells. If successful, this approach will significantly improve the survival of ovarian cancer patients with desirable clinical safety.