Site-specifically labeled antibody-drug conjugate for simultaneous therapy and immunoPET Journal Article
| Authors: | Adumeau, P.; Vivier, D.; Sharma, S. K.; Wang, J.; Zhang, T.; Chen, A.; Agnew, B. J.; Zeglis, B. M. |
| Article Title: | Site-specifically labeled antibody-drug conjugate for simultaneous therapy and immunoPET |
| Abstract: | 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. © 2018 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; positron emission tomography; antineoplastic agent; mouse; animal tissue; tumor volume; epidermal growth factor receptor 2; animal experiment; animal model; in vivo study; antineoplastic activity; in vitro study; tumor xenograft; drug design; drug synthesis; immunoreactivity; isotope labeling; single drug dose; antibody specificity; therapy effect; tracer; trastuzumab; pet; surface plasmon resonance; deferoxamine; radiochemistry; click chemistry; cycloaddition; alkyne; glycan; adc; azide; complementarity determining region; immunoglobulin fc fragment; human epidermal growth factor receptor 2 positive breast cancer; heavy chain; human; priority journal; article; vedotin; site-specific bioconjugation; antibodyâdrug conjugate; heavy chain glycans; strain-promoted azideâalkyne click chemistry; antibody drug conjugate; trastuzumab monomethyl auristatin e immunoconjugate; zirconium 89 trastuzumab immunoconjugate; zirconium 89 trastuzumab monomethyl auristatin e immunoconjugate |
| Journal Title: | Molecular Pharmaceutics |
| Volume: | 15 |
| Issue: | 3 |
| ISSN: | 1543-8384 |
| Publisher: | American Chemical Society |
| Date Published: | 2018-03-05 |
| Start Page: | 892 |
| End Page: | 898 |
| Language: | English |
| DOI: | 10.1021/acs.molpharmaceut.7b00802 |
| PROVIDER: | scopus |
| PUBMED: | 29356543 |
| PMCID: | PMC6466629 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 April 2018 -- Source: Scopus |
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