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Cancer Cell. 2016 Jan 11;29(1):117-29. doi: 10.1016/j.ccell.2015.12.008.

A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy.

Author information

1
Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA. Electronic address: lij@medimmune.com.
2
Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA.
3
Oncology, MedImmune LLC, Gaithersburg, MD 20878, USA.
4
Biologics Safety Assessment, MedImmune LLC, Gaithersburg, MD 20878, USA.
5
Antibody Discovery & Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
6
Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA; MedImmune Ltd, Granta Park, Cambridge CB21 6GH, UK.

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.

PMID:
26766593
DOI:
10.1016/j.ccell.2015.12.008
[Indexed for MEDLINE]
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