MORAb-202, an Antibody–Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity

Abstract

Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG 2 -valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

A Fluorescent Probe for Rapid, High‐Contrast Visualization of Folate‐Receptor‐Expressing Tumors In Vivo

“…However, although it was confirmed to be safe, anti‐FRs antibody did not meet the primary endpoints of progression‐free survival or overall survival in a clinical trial. Therefore, anti‐FRs antibody–drug conjugates (ADCs) have been developed in order to enhance the efficacy . However, poor penetration into solid tumors still poses a problem for ADCs as well as naked therapeutic antibodies.…”

Antibody–Prodrug Conjugates with KSP Inhibitors and Legumain‐Mediated Metabolite Formation

“…To achieve an additional safety level, an ew class of antibody-prodrug conjugates (APDCs) directeda gainst different targets in solid tumors is here described. [7] The goal of the currentw ork is to achieve the formation of active metabolites in tumors with an additional discriminationtohealthy organs and tissues. Legumain-activatable APDCs were as potent as their cathepsin B-activatable analogues.…”

“…[7] The goal of the currentw ork is to achieve the formation of active metabolites in tumors with an additional discriminationtohealthy organs and tissues. It shows an increased expression and, thus, higher activityi ns olid tumors compared to most healthyt issues.L egumain is the only asparaginyl endopeptidase in mammals.…”

“…It shows an increased expression and, thus, higher activityi ns olid tumors compared to most healthyt issues.L egumain is the only asparaginyl endopeptidase in mammals. [7] The goal of the currentw ork is to achieve the formation of active metabolites in tumors with an additional discriminationtohealthy organs and tissues. [5d, 6] However,t hose approaches required higher doses of conjugates,p robablyd ue to suboptimal activation, and they bear as ubstantial risk of side effectsd ue to the release and redistribution of permeable toxophores into the circulation.…”

“…Consideringt hat ADCs are delivered to acidic lysosomal compartments of tumor cells in which legumain activity is the highest also compared to healthy tissues, al egumain-mediated ADC metabolism has been explored. [7] The goal of the currentw ork is to achieve the formation of active metabolites in tumors with an additional discriminationtohealthy organs and tissues. Furthermore, when delivered through ADCs the profile of the released metabolites can be designed with high flexibility,f or example, for low membrane permeability leadingt oalong lastingi ntracellular exposure.We have previously described the discovery of ADCs with kinesin spindle protein inhibitor (KSPi)p ayloadsa nd found particularly the ADC 3a in combination with the TWEAKR antibody BAY-356 (TPP-2658) to be highly potent in vitro and in vivo against TWEAKR-expressing solid-tumor models [8] (Scheme 1).…”