Novel Platform to achieve high avidity of heterodimers for targeted cancer imaging

Oregon Health & Science University, Portland OR

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Abstract

? DESCRIPTION (provided by applicant): Targeted cancer imaging is critical for fundamental improvements in cancer patient care and current imaging quality and diagnosis accuracy rely heavily on the affinity/specificity between the targeted biomarker and targeting ligand (small molecules, peptides and antibodies). A heterodimeric ligand that simultaneously associates two linked ligands with two different targeting biomarkers provides a broadly applicable approach to convert low affinity ligands (Kdaffinity ~ mM - µM) to the one with high avidity/specificity (Kdavidity ~ nM). Such high avidity heterodimers are usually pursued by: 1) synthesizing a number of heterodimers with different linkers; and 2) measuring their in vitro avidities individually. However the type of cancer cells may vary in different labs and then the receptors density and distance varies accordingly, so that avidity measurements and heterodimer library synthesis (if such a library is not available in the lab) need to be conducted individually again. Even more disappointing is the fact that, once the receptor of interest changes, repeating the entire procedure (including new heterodimer library synthesis and avidity measurement) is required. Therefore, a lack of a generic and rapid optimization platform has been considered as one of the major barriers for the widespread and routine utilization of heterodimeric ligand for preclinical and/or clinical studies. In order to overcome this problem, we propose the first, high-throughput platform for the easy preparation of high avidity heterodimers, which can be broadly applied to various dual-biomarker combinations and different tumors. Such widespread applicable technology will significantly accelerate and/or enhance targeted cancer imaging using heterodimers, particularly in the following situations: 1) targeted biomarker(s) which are expressed in low abundance; and 2) situations where no high affinity (and/or specificity) monovalent ligands are available.