Use of Morpholino Oligomers for Pretargeting

Abstract

Differing from the conventional direct-targeting strategy in which a probe or payload is directly loaded onto a targeting molecule that binds to the native target, pretargeting is an improved targeting strategy. It converts the native target to an artificial target specific for a secondary targeting molecule loaded with the probe or payload (effector). The effector is small and does not accumulate in normal tissues, which accelerates the targeting process and generates high target to nontarget ratios. DNA/cDNA analogs can serve as the recognition pair, i.e., the artificial target and the secondary targeting effector. Morpholino oligomers are so far the most investigated and the most successful DNA/cDNA analog recognition pairs for pretargeting. Herein, we describe the pretargeting principles, the pretargeting strategy using Morpholino oligomers, and the preclinical success so far achieved.

DNA‐Targeted Complexes of Tc and Re for Biomedical Applications

“…[135][136][137][138]140] Later on, Liu and co-workers studied in detail the principles of the pretargeting strategy using morpholino oligomers, as illustrated in Figure 20. [144] In this approach, the chain length and base sequence of the radiolabeled oligomers might have a critical influence on the observed biological performance. For instance, Liu et al demonstrated that by choosing a cytosinefree base sequence, kidney accumulation of a 99m Tc labeled Phosphodiester DNA single strain 5'-biotinTAATACGACTCACTATAGGGAGamine-3' 5'-amineGGTACAGGTCTCACTGTATGACbiotin-3' and respective complements 99m Tc 3' Hexylamine or 5' Hexylamine HYNIC (glucoheptonate) [125] 5'-biotinTAATACGACTCACTATAGGGAGamine-3' and its complement 99m Tc 3' Hexylamine S-Acetyl-NHS-MAG 3 [126] Phosphorothioate (PS) or Phosphodiester DNA single strain 5'-biotinGGTACAGGTCTCACTGTATGACamine-3' 99m Tc 3' Hexylamine HYNIC (tricine) [127] Phosphorothioate (PS) antisense 5'-GCGTGCCTCCTCACTGGC-3' sense 5'-GCCAGTGAGGAGGCACGC-3' 99m Tc 5' Hexylamine HYNIC(tricine) S-Acetyl-NHS-MAG 3 DTPA anhydride [128] antisense 5'-GCGTGCCTCCTCACTGGC-3' sense 5'-GCCAGTGAGGAGGCACGC-3' random 5'-GGGATCGTTCAGAGTCTA-3' cMORF oligomer can be reduced without adversely influencing tumor accumulation using the pretargeting strategy.…”

A Revisit to the Pretargeting Concept—A Target Conversion

“…Our choice of MORFs was only based on their better solubility, slightly lower liver accumulation, and easier availability to us (Mang'era et al, 2001). MORF/cMORF pretargeting has been very successful preclinically for both imaging and therapy (Liu et al, 2006, 2008a, 2010a,c, 2011, 2012; Liu, 2017). Very recently, a Sweden group has achieved similar successes using the PNAs (Westerlund et al, 2015, 2018; Honarvar et al, 2016; Altai et al, 2017).…”

Pretargeted Alpha Therapy of Disseminated Cancer Combining Click Chemistry and Astatine-211

“…Today, several pretargeting strategies can be used to combine antibodies and radioligands in vivo; some of them utilize a noncovalent interaction such as streptavidinbiotin [9][10][11], and some utilize the hybridization of complementary oligonucleotides [12,13] or the ability of bispecific antibodies [14,15] to bind an antigen and a radiolabeled hapten. Last but not least, there is the biorthogonal inverse electron demand Diels-Alder (IEDDA) click reaction, which utilizes the fast and highly specific reaction that occurs between a diene, such as 1,2,4,5-tetrazine (Tz), and a dienophile, particularly trans-cyclooctene (TCO), which appears to be seven times more reactive than the cis-cyclooctene (CCO) in the IEDDA reaction [15][16][17][18][19].…”