title: A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy.
abstract: Antibody-drug conjugate (ADC) which delivers cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking has emerged as an effective cancer therapy. We show that a bivalent biparatopic antibody targeting two non-overlapping epitopes on HER2 can induce HER2 receptor clustering, which in turn promotes robust internalization, lysosomal trafficking, and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic ADC demonstrates superior anti-tumor activity over ado-trastuzumab emtansine (T-DM1) in tumor models representing various patient subpopulations, including T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory. Our findings indicate that this biparatopic ADC has promising potential as an effective therapy for metastatic breast cancer and a broader patient population may benefit from this unique HER2-targeting ADC.
authors.affiliation: Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA. Electronic address: lij@medimmune.com.
authors.forename: John Y
authors.initials: JY
authors.lastname: Li
authors.affiliation: Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Perry
authors.affiliation: Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Muniz-Medina
authors.affiliation: Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Oncology, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Leslie K
authors.initials: LK
authors.lastname: Wetzel
authors.affiliation: Biologics Safety Assessment, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Marlon C
authors.initials: MC
authors.lastname: Rebelatto
authors.affiliation: Biologics Safety Assessment, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Mary Jane Masson
authors.initials: MJ
authors.lastname: Hinrichs
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Binyam Z
authors.initials: BZ
authors.lastname: Bezabeh
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Fleming
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Dimasi
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Feng
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Dorin
authors.initials: D
authors.lastname: Toader
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Andy Q
authors.initials: AQ
authors.lastname: Yuan
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Lin
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Changshou
authors.initials: C
authors.lastname: Gao
authors.affiliation: Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Herren
authors.initials: H
authors.lastname: Wu
authors.affiliation: Biologics Safety Assessment, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Dixit
authors.affiliation: Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA; MedImmune Ltd, Granta Park, Cambridge CB21 6GH, UK.
authors.forename: Jane K
authors.initials: JK
authors.lastname: Osbourn
authors.affiliation: Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Coats
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000922:Immunotoxins; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab