Site-specifically labeled antibody–drug conjugate for simultaneous therapy and immunoPET

P Adumeau, D Vivier, SK Sharma, J Wang… - Molecular …, 2018 - ACS Publications
P Adumeau, D Vivier, SK Sharma, J Wang, T Zhang, A Chen, BJ Agnew, BM Zeglis
Molecular pharmaceutics, 2018ACS Publications
The 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 …
The 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.
ACS Publications
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