Antibody-drug conjugate MORAb-202 exhibits long-lasting antitumor efficacy in TNBC PDx models
Keiji Furuuchi1, Katherine Rybinski1, James Fulmer1
1Epochal Precision Anti-Cancer Therapeutics (EPAT), Eisai Inc, Exton, PA, USA.
Abstract:
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. MORAb-202 was highly cytotoxic to FRA-positive cells in vitro, with limited off-target killing of FRA-negative cells. Furthermore, MORAb-202 showed a clear in vitro bystander cytotoxic effect in coculture with FRA-positive/negative cells. In vivo antitumor efficacy studies of MORAb-202 were conducted with a single administration of MORAb-202 in triple-negative breast cancer (TNBC) patient-derived xenograft (PDx) models expressing low and high levels of FRA. MORAb-202 exhibited durable efficacy proportional to tumor FRA expression. Toxicology studies (Q3Wx2) in nonhuman 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.
Insights
The investigational antibody-drug conjugate MORAb-202 shows promise for treating triple-negative breast cancer (TNBC). It effectively targets folate receptor alpha (FRA)-positive tumors with minimal off-target effects and demonstrates durable antitumor efficacy in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Folate receptor alpha (FRA) is overexpressed in several cancer types, making it a target for cancer therapies.
- Antibody-drug conjugates (ADCs) offer targeted delivery of cytotoxic agents to cancer cells.
Purpose of the Study:
- To evaluate the preclinical efficacy and safety of MORAb-202, an ADC targeting FRA.
- To assess MORAb-202's in vitro and in vivo activity, including its bystander effect and toxicity profile.
Main Methods:
- In vitro cytotoxicity assays on FRA-positive and FRA-negative cells.
- Coculture experiments to evaluate bystander effect.
- In vivo antitumor efficacy studies in triple-negative breast cancer (TNBC) patient-derived xenograft (PDx) models.
- Toxicology studies in nonhuman primates.
Main Results:
- MORAb-202 demonstrated high in vitro cytotoxicity against FRA-positive cells with limited off-target effects.
- A significant in vitro bystander cytotoxic effect was observed.
- MORAb-202 exhibited durable, dose-dependent antitumor efficacy in TNBC PDx models.
- Hematologic toxicity was identified as the primary concern in nonhuman primate toxicology studies.
Conclusions:
- MORAb-202 is a potent ADC targeting FRA, showing promising preclinical efficacy in TNBC models.
- The observed efficacy and manageable toxicity profile support further investigation of MORAb-202 for TNBC treatment.
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