Generation and activity of a humanized monoclonal antibody that selectively neutralizes the epidermal growth factor receptor ligands transforming growth factor-α and epiregulin.

At least 7 distinct EGF ligands bind to and activate the EGF receptor (EGFR). This activation plays important roles in the embryo and in maintenance of adult tissues. Importantly, pharmacologic EGFR inhibition has revealed that it also plays critical roles in the pathophysiology of diverse disease states, especially cancer. The roles of specific EGFR ligands are poorly defined in these disease states. Accumulating evidence suggests a role for transforming growth factor alpha (Tgfa) in skin, lung and kidney disease. In order to explore the role of Tgfa, we generated a monoclonal antibody (mAb41) that binds to and neutralizes human Tgfa with high affinity (KD = 36.5 pM). The antibody also binds human Epiregulin (Ereg) (KD = 346.6 pM) and inhibits ligand induced HT-29 cell proliferation (IC50 values of 0.52 nM and 1.12 nM for human Tgfa and Ereg respectively). In vivo, a single administration of the antibody to pregnant mice (30 mg/kg subcutaneous at day 14 post plug) or weekly administration to neonate mice (20 mg/kg subcutaneous for 4 weeks) phenocopy Tgfa knockout mice with curly whiskers, stunted growth and expansion of the hypertrophic zone of growth plate cartilage. Humanization of this monoclonal antibody to a human IgG4 antibody (LY3016859) enables clinical development. Importantly, administration of the humanized antibody to cynomolgus monkeys is absent of the skin toxicity observed with current EGFR inhibitors used clinically and no other pathologies were noted, indicating that neutralization of Tgfa could provide a relatively safe profile as it advances in clinical development.