Journal
MOLECULAR PHARMACEUTICS
Volume 15, Issue 3, Pages 892-898Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.7b00802
Keywords
antibody-drug conjugate; ADC; positron emission tomography; PET; site-specific bioconjugation; heavy chain glycans; click chemistry; strain promoted azide-alkyne click chemistry
Funding
- NIH [R24 CA83084, P30 CA08748]
- National Institutes of Health [4R00CA178205-02, R01204167]
- Team Connor Childhood Cancer Foundation
- National Institute on Minority Health and Health Disparities [G12MD007599]
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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 F-c 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 longlived positron-emitting radiometal Zr-89 (t(1/2) approximate to 3.3 days). Both the tumor targeting and therapeutic efficacy of the Zr-89-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 similar to 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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