title: XGFR*, a novel affinity-matured bispecific antibody targeting IGF-1R and EGFR with combined signaling inhibition and enhanced immune activation for the treatment of pancreatic cancer.
abstract: The epidermal growth factor receptor (EGFR) and the insulin-like growth factor-1 receptor (IGF-1R) play critical roles in tumor growth, providing a strong rationale for the combined inhibition of IGF-1R and EGFR signaling in cancer therapy. We describe the design, affinity maturation, in vitro and in vivo characterization of the bispecific anti-IGF-1R/EGFR antibody XGFR*. XGFR* is based on the bispecific IgG antibody XGFR, which enabled heterodimerization of an IGF-1R binding scFab heavy chain with an EGFR-binding light and heavy chain by the "knobs-into-holes" technology. XGFR* is optimized for monovalent binding of human EGFR and IGF-1R with increased binding affinity for IGF-1R due to affinity maturation and highly improved protein stability to oxidative and thermal stress. It bears an afucosylated Fc-portion for optimal induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Stable Chinese hamster ovary cell clones with production yields of 2-3 g/L were generated, allowing for large scale production of the bispecific antibody. XGFR* potently inhibits EGFR- and IGF-1R-dependent receptor phosphorylation, reduces tumor cell proliferation in cells with heterogeneous levels of IGF-1R and EGFR receptor expression and induces strong ADCC in vitro. A comparison of pancreatic and colorectal cancer lines demonstrated superior responsiveness to XGFR*-mediated signaling and tumor growth inhibition in pancreatic cancers that frequently show a high degree of IGF-1R/EGFR co-expression. XGFR* showed potent anti-tumoral efficacy in the orthotopic MiaPaCa-2 pancreatic xenograft model, resulting in nearly complete tumor growth inhibition with significant number of tumor remissions. In summary, the bispecific anti-IGF-1R/EGFR antibody XGFR* combines potent signaling and tumor growth inhibition with enhanced ADCC induction and represents a clinical development candidate for the treatment of pancreatic cancer.
authors.affiliation: a Roche Pharma Research and Early Development, Roche Innovation Center Munich , Nonnenwald, Penzberg , Germany.
authors.forename: Juergen M
authors.initials: JM
authors.lastname: Schanzer
authors.affiliation: a Roche Pharma Research and Early Development, Roche Innovation Center Munich , Nonnenwald, Penzberg , Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wartha
authors.affiliation: b Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Wagistrasse, Schlieren , Switzerland.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Moessner
authors.affiliation: b Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Wagistrasse, Schlieren , Switzerland.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Hosse
authors.affiliation: b Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Wagistrasse, Schlieren , Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Moser
authors.affiliation: a Roche Pharma Research and Early Development, Roche Innovation Center Munich , Nonnenwald, Penzberg , Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Croasdale
authors.affiliation: b Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Wagistrasse, Schlieren , Switzerland.
authors.forename: Halina
authors.initials: H
authors.lastname: Trochanowska
authors.affiliation: c Pharma Research and Early Development, Roche Innovation Center Shanghai , Cai Lun Road, Shanghai , China.
authors.forename: Cuiying
authors.initials: C
authors.lastname: Shao
authors.affiliation: c Pharma Research and Early Development, Roche Innovation Center Shanghai , Cai Lun Road, Shanghai , China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: c Pharma Research and Early Development, Roche Innovation Center Shanghai , Cai Lun Road, Shanghai , China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: b Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Wagistrasse, Schlieren , Switzerland.
authors.forename: Tina
authors.initials: T
authors.lastname: Weinzierl
authors.affiliation: a Roche Pharma Research and Early Development, Roche Innovation Center Munich , Nonnenwald, Penzberg , Germany.
authors.forename: Natascha
authors.initials: N
authors.lastname: Rieder
authors.affiliation: b Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Wagistrasse, Schlieren , Switzerland.
authors.forename: Marina
authors.initials: M
authors.lastname: Bacac
authors.affiliation: a Roche Pharma Research and Early Development, Roche Innovation Center Munich , Nonnenwald, Penzberg , Germany.
authors.forename: Carola H
authors.initials: CH
authors.lastname: Ries
authors.affiliation: a Roche Pharma Research and Early Development, Roche Innovation Center Munich , Nonnenwald, Penzberg , Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Kettenberger
authors.affiliation: a Roche Pharma Research and Early Development, Roche Innovation Center Munich , Nonnenwald, Penzberg , Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Schlothauer
authors.affiliation: a Roche Pharma Research and Early Development, Roche Innovation Center Munich , Nonnenwald, Penzberg , Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Friess
authors.affiliation: b Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Wagistrasse, Schlieren , Switzerland.
authors.forename: Pablo
authors.initials: P
authors.lastname: Umana
authors.affiliation: b Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Wagistrasse, Schlieren , Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000494:pharmacology*; D000915:Antibody Affinity; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000276:immunology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1
keywords: ADCC; Bispecific antibody; EGFR; IGF-1R; pancreatic cancer