title: Generation and activity of a humanized monoclonal antibody that selectively neutralizes the epidermal growth factor receptor ligands transforming growth factor-α and epiregulin.
abstract: At least seven distinct epidermal growth factor (EGF) ligands bind to and activate the EGF receptor (EGFR). This activation plays an important role in the embryo and in the maintenance of adult tissues. Importantly, pharmacologic EGFR inhibition also plays a critical role 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 α (TGFα) in skin, lung, and kidney disease. 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 myofibroblast cell proliferation (IC50 values of 0.52 and 1.12 nM for human Tgfa and Ereg, respectively). In vivo, a single administration of the antibody to pregnant mice (30 mg/kg s.c. at day 14 after plug) or weekly administration to neonate mice (20 mg/kg s.c. 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.
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Catherine B
authors: CB
authors: Beidler
authors: Ramona J
authors: RJ
authors: Petrovan
authors: Elaine M
authors: EM
authors: Conner
authors: Jeffrey S
authors: JS
authors: Boyles
authors: Derek D
authors: DD
authors: Yang
authors: Shannon M
authors: SM
authors: Harlan
authors: Shaoyou
authors: S
authors: Chu
authors: Bernice
authors: B
authors: Ellis
authors: Amita
authors: A
authors: Datta-Mannan
authors: Robert L
authors: RL
authors: Johnson
authors: Anja
authors: A
authors: Stauber
authors: Derrick R
authors: DR
authors: Witcher
authors: Matthew D
authors: MD
authors: Breyer
authors: Josef G
authors: JG
authors: Heuer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D007074:Immunoglobulin G; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors