mp7b00802_si_001.pdf (2.61 MB)
Site-Specifically Labeled Antibody–Drug Conjugate for Simultaneous Therapy and ImmunoPET
journal contribution
posted on 2018-01-22, 00:00 authored by Pierre Adumeau, Delphine Vivier, Sai Kiran Sharma, Jessica Wang, Terry Zhang, Aimei Chen, Brian J. Agnew, Brian M. ZeglisThe
conjugation of antibodies with cytotoxic drugs can alter their in vivo pharmacokinetics. As a result, the careful assessment
of the in vivo behavior, and specifically the tumor-targeting
properties, of antibody–drug conjugates represents a crucial
step in their development. In order to facilitate this process, we
have created a methodology that facilitates the dual labeling of an
antibody with both a toxin and a radionuclide for positron emission
tomography (PET). To minimize the impact of these modifications, this
chemoenzymatic approach leverages strain-promoted azide–alkyne
click chemistry to graft both cargoes to the heavy chain glycans of
the immuoglobulin’s Fc domain. As a proof-of-concept,
a HER2-targeting trastuzumab immunoconjugate was created bearing both
a monomethyl auristatin E (MMAE) toxin as well as the long-lived positron-emitting
radiometal 89Zr (t1/2 ≈
3.3 days). Both the tumor targeting and therapeutic efficacy of the 89Zr-trastuzumab-MMAE immunoconjugate were validated in vivo using a murine model of HER2-expressing breast cancer.
The site-specifically dual-labeled construct enabled the clear visualization
of tumor tissue via PET imaging, producing tumoral uptake of ∼70%ID/g.
Furthermore, a longitudinal therapy study revealed that the immunoconjugate
exerts significant antitumor activity, leading to a >90% reduction
in tumor volume over the course of 20 days.
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HER 2-targeting trastuzumab immunoconjugatemonomethyl auristatin Etumor volumetumor-targeting propertiessite-specifically dual-labeledSimultaneous Therapyantitumor activityPET imagingmurine modelpositron emission tomographytumor tissuepositron-emitting radiometal 89 Zrtherapy studyantibodycytotoxic drugsHER 2-expressing breast cancertumoral uptake89 Zr-trastuzumab-MMAE immunoconjugatevivo pharmacokineticschain glycans20 daystoxinIDvivo behavior
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