![]() ![]() A Good Laboratory Practice-compliant tissue cross-reactivity study of MEDI-547 conducted on a full panel of normal human tissues from 3 donors demonstrated rare, weak staining of the epithelium of tonsilar crypts and esophageal mucosa, and occasional, weak cytoplasmic staining of placental trophoblastic epithelium. Ī primary concern for any new targeted cancer therapy is the range and sensitivity of potentially susceptible tissues, both normal and malignant. Upon internalization of MEDI-547, cysteine (cys)-mcMMAF is released from 1C1 by lysosomal degradation of the antibody component, inducing cell cycle arrest at the G2 – M border, microtubule disruption, and apoptotic cell death. MEDI-547 binds human, cynomolgus monkey, mouse, and rat EphA2 with similar binding affinities via the highly conserved extracellular domain (MedImmune, LLC, data on file). Auristatin is a microtubule inhibitor that binds to the vinca alkaloid-binding domain, and has been shown to exhibit potent anticancer effects in preclinical and clinical studies. The antibody has no antitumor effects when unconjugated thus, it was intended to be used to deliver highly toxic chemotherapy directly to EphA2-expressing cancer cells. MEDI-547 is an ADC composed of a human immunoglobulin (Ig) G1 monoclonal antibody directed against EphA2 (known as 1C1) and conjugated on cysteine residues to an auristatin derivative linker-toxin maleimidocaproyl-monomethyl auristatin phenylalanine (mcMMAF). In addition to serving as a direct target, EphA2 could be used as a cancer-related protein for antibody-targeting therapy, particularly antibody-drug conjugate (ADC)-based therapies, in which chemical toxins or radioligands are covalently added to the antibody structure. ![]() Collectively, these findings suggest that EphA2 may be an ideal tumor target for cancer therapy. EphA2 overexpression in several types of cancers has been correlated with poor patient outcome. While EphA2 is expressed at relatively low levels in normal adult tissues, it is overexpressed in a number of carcinomas, including ovarian, endometrial, and cervical cancers melanoma and gliomas. These events occur through the interaction of the Eph receptors with their ligands, the ephrins, that are anchored to the membrane of adjacent cells. Conclusions The safety profile of MEDI-547 does not support further clinical investigation in patients with advanced solid tumors.Įphrin type-A receptor 2 (EphA2), a member of the Eph family of receptor tyrosine kinases, is involved in developmental cell-to-cell interactions and cell migration processes, including angiogenesis and neural crest cell migration. No accumulation of MEDI-547 was observed at 0.08 mg/kg upon administration of a second dose 3 weeks following dose 1. Serum MEDI-547 concentrations decreased rapidly, ~70% by 3 days post-dose. Minimal or no dissociation of toxin from 1C1 conjugate occurred in the blood. Best response included progressive disease ( n = 5 83.3%) and stable disease ( n = 1 16.7%). Three patients (50%) experienced treatment-related serious AEs, including conjunctival hemorrhage, pain (led to study drug discontinuation), liver disorder, and hemorrhage. The most frequently reported treatment-related adverse events (AEs) were increased liver enzymes, decreased hemoglobin, decreased appetite, and epistaxis. Therefore, lower doses were not explored and an MTD could not be selected. The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events (hemorrhage-related, n = 3 epistaxis, n = 2). Results Six patients received 0.08 mg/kg all discontinued treatment. Methods In this phase 1, open-label study with planned dose-escalation and dose-expansion cohorts, patients received a 1-h intravenous infusion of MEDI-547 (0.08 mg/kg) every 3 weeks. We aimed to evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of MEDI-547, an antibody drug conjugate composed of the cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal antibody (1C1), in patients with solid tumors relapsed/refractory to standard therapy. Background Targeting the cell-surface receptor EphA2, which is highly expressed in some solid tumors, is a novel approach for cancer therapy.
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