MORAb-202 is an antibody–drug conjugate comprised of the humanized anti-folate receptor-alpha (FRα) monoclonal antibody, farletuzumab, conjugated to the cytotoxic microtubule inhibitor, eribulin. In a phase 1 study (NCT03386942), MORAb-202 showed antitumor activity across varying FRα-expression levels at doses of 0.9 mg/kg (cohort 1) and 1.2 mg/kg (cohort 2) in patients with platinum-resistant (PR) OV. The disease control rate was 66.7% in cohort 1 and 95.2% in cohort 2. To evaluate the antitumor activity of MORAb-202 against high-grade serous OV, we investigated its biological mechanism of action, focusing on its ability to induce ICD using in vitro and in vivo models.
In vitro induction of ICD was evaluated in human OV cell lines treated with either MORAb-202 or eribulin by measuring HMGB1, HSP70, HSP90, and calreticulin. Antitumor activity of MORAb-202 was examined in OV cell line derived xenografts (CDx), and platinum sensitive (Pt-S) and platinum refractory (Pt-R) OV patient-derived xenografts (PDx). Immunohistochemistry/immunofluorescence (IHC/IF) staining in an OV CDx model was used to assess target engagement (anti-eribulin) and in vivo ICD induction (anti-HMGB1, anti-HSP90).
Both eribulin and MORAb-202 elicited in vitro ICD induction of HMGB1, calreticulin, HSP70, and HSP90. HMGB1 increased in a dose-dependent manner; a time-course study in multiple cell lines showed this release to occur 72 hrs post treatment. In OV CDx and PDx models, a single dose of MORAb-202 (5 mg/kg) showed notable tumor shrinkage which was superior to eribulin monotherapy at a dose of 3.2 mg/kg (32 times the molar equivalent of eribulin in a 5 mg/kg dose of MORAb-202). A higher dosage of MORAb-202 (12.5 mg/kg) was required for durable tumor shrinkage in the Pt-R OV PDx model. In an OV CDx model, target engagement of MORAb-202 was confirmed. Translocation of HMGB1 and enhanced HSP90 production as ICD biomarkers were observed in triplicate tumor samples treated with MORAb-202 and eribulin.
These preclinical data illustrate ICD as a notable mode of action of MORAb-202 and suggest potential for effective antitumor activity in the clinic.
Editorial support was provided by Dolly Al Koborssy, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Eisai Inc., Nutley, NJ, USA.