A biorthogonal chemistry approach for high-contrast antibody imaging of lymphoma at early time points

• DOI: 10.1186/s13550-025-01213-x
• Publication Date: 2025-03-24T00:30:51Z
• Authors: Swarbhanu Sarkar; Jonathan M. Pham; Kimberly J. Edwards; Nitika Sharma; Kexiang Xu; A. Paden King; Andres Fernandez ...; Michael D. Farwell; Daniel A. Pryma; Stephen J. Schuster; Mark A. Sellmyer
• Keywords: Cardiac Imaging

Monoclonal antibodies are highly specific for their targets making them effective cancer therapy. However, large molecular weight causes slow blood clearance, often requiring weeks to be removed from circulation. This limitation affects companion nuclear imaging and antibody-based diagnostics, necessitating delayed imaging. We report the expansion of a methodology improving positron emission tomography (PET) contrast lymphoma biomarker CD20 at early time points after radiolabeled antibody administration. Intact radioimmunoconjugates allowed stay in circulation long enough accumulate tumors, then, using chemical trigger, we induced rapid clearance radioactivity non-target tissues by cleaving linker between radioactivity. For brevity, refer this as Tetrazine KnockOut (TKO) method which uses transcyclooctene-tetrazine (TCO-Tz) reaction, wherein an is conjugated with containing TCO radioisotope. optimized several different radioisotopes evaluated ability tetrazines knockout circulating antibodies. explored cell types varying internalization rates, characterize parameters TKO tested [89Zr]Zr-DFO-TCO-rituximab model PET Tz or vehicle Treatment > 70% cleavage vitro within 30 min. Internalizing exhibited similar cellular uptake compared vehicle, whereas decreased was seen slowly internalizing In rodents, rapidly liberated antibody, cleared blood, accumulated bladder. resulted 50% organs following injection. No decrease tumor observed when rate higher model, target-to-background ratio increased twofold comparison nontreated groups 24 h. The approach potentiates rituximab has translational potential