Over the past ten years, 89Zr-labeled antibodies have emerged as very promising radiopharmaceuticals for the PET imaging of cancer. For example, both 89Zr-DFO-trastuzumab and 89Zr-DFO-pertuzumab - two antibodies targeting different epitopes of HER2 - have recently showed significant clinical potential for the PET imaging of patients with HER2-positive breast cancer. However, despite the promise of 89Zr-labeled antibodies, the current synthetic methodology used to create these radioimmunoconjugates prevent them from reaching their maximum potential in the clinic. Specifically, the conjugation step between the amine-reactive chelator and one of the antibody lysines results in poorly defined and heterogeneous constructs. Indeed, antibodies have many lysines and it is impossible to control the molecular location of this reaction or the number of chelators attached to the antibody. In the last few years, site-specifically conjugations have emerged as a way to address these issues. In this work, we compare the in vivo behavior of two pertuzumab-based radioimmunoconjugates that have been site-specifically modified with DFO on the heavy glycans with a randomly labeled variant synthesized using traditional methods. The site-specific constructs were obtained using two click chemistry-based chemoenzymatic strategies previously developed in our laboratory. Imaging and biodistribution studies in nude mice bearing subcutaneous HER2-expressing BT474 xenografts showed that while the activity concentrations in the tumor were similar for all three constructs, the activity concentrations in some non-target tissues (specifically bone or liver) were significantly lower for the site-specific radioimmunoconjugates. These three constructs will soon be evaluated in humanized mice bearing BT474 tumors, paving the way for the eventual clinical translation of the site-specifically modified radioimmunoconjugates.

Influence of chelator conjugation method on immunoPET imaging

255th National Meeting (2018)

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