title: A HER2-specific Modified Fc Fragment (Fcab) Induces Antitumor Effects Through Degradation of HER2 and Apoptosis.
abstract: FS102 is a HER2-specific Fcab (Fc fragment with antigen binding), which binds HER2 with high affinity and recognizes an epitope that does not overlap with those of trastuzumab or pertuzumab. In tumor cells that express high levels of HER2, FS102 caused profound HER2 internalization and degradation leading to tumor cell apoptosis. The antitumor effect of FS102 in patient-derived xenografts (PDXs) correlated strongly with the HER2 amplification status of the tumors. Superior activity of FS102 over trastuzumab or the combination of trastuzumab and pertuzumab was observed in vitro and in vivo when the gene copy number of HER2 was equal to or exceeded 10 per cell based on quantitative polymerase chain reaction (qPCR). Thus, FS102 induced complete and sustained tumor regression in a significant proportion of HER2-high PDX tumor models. We hypothesize that the unique structure and/or epitope of FS102 enables the Fcab to internalize and degrade cell surface HER2 more efficiently than standard of care antibodies. In turn, increased depletion of HER2 commits the cells to apoptosis as a result of oncogene shock. FS102 has the potential of a biomarker-driven therapeutic that derives superior antitumor effects from a unique mechanism-of-action in tumor cells which are oncogenically addicted to the HER2 pathway due to overexpression.
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Kin-Mei
authors.initials: KM
authors.lastname: Leung
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK. Electronic address: sarah.batey@f-star.com.
authors.forename: Sarah
authors.initials: S
authors.lastname: Batey
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Rowlands
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Samine J
authors.initials: SJ
authors.lastname: Isaac
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Phil
authors.initials: P
authors.lastname: Jones
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Drewett
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Carvalho
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Miguel
authors.initials: M
authors.lastname: Gaspar
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weller
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Medcalf
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Mateusz M
authors.initials: MM
authors.lastname: Wydro
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Pegram
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Geert C
authors.initials: GC
authors.lastname: Mudde
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Anton
authors.initials: A
authors.lastname: Bauer
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Moulder
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Max
authors.initials: M
authors.lastname: Woisetschläger
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Mihriban
authors.initials: M
authors.lastname: Tuna
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: John S
authors.initials: JS
authors.lastname: Haurum
authors.affiliation: F-star Biotechnology Ltd, Babraham Research Campus, Cambridge, UK.
authors.forename: Haijun
authors.initials: H
authors.lastname: Sun
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction; D000068878:Trastuzumab / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007141:Immunoglobulin Fc Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C000610756:FS102 antibody fragment; C485206:pertuzumab