1. Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-Phosphorodiamidate Morpholino Oligomer Conjugates for Drug Development.
- Author
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Cochran M, Marks I, Albin T, Arias D, Kovach P, Darimont B, Huang H, Etxaniz U, Kwon HW, Shi Y, Diaz M, Tyaglo O, Levin A, and Doppalapudi VR
- Subjects
- Animals, Structure-Activity Relationship, Mice, Drug Development, Dystrophin metabolism, Dystrophin genetics, Immunoconjugates chemistry, Immunoconjugates pharmacology, Immunoconjugates pharmacokinetics, Humans, Male, Mice, Inbred C57BL, Oligonucleotides chemistry, Oligonucleotides pharmacokinetics, Muscle, Skeletal metabolism, Receptors, Transferrin metabolism, Receptors, Transferrin immunology, Morpholinos chemistry, Morpholinos pharmacology, Morpholinos pharmacokinetics, Mice, Inbred mdx, Muscular Dystrophy, Duchenne drug therapy
- Abstract
Antibody-oligonucleotide conjugates (AOCs) are promising treatments for Duchenne muscular dystrophy (DMD). They work via induction of exon skipping and restoration of dystrophin protein in skeletal and heart muscles. The structure-activity relationships (SARs) of AOCs comprising antibody-phosphorodiamidate morpholino oligomers (PMOs) depend on several aspects of their component parts. We evaluate the SAR of antimouse transferrin receptor 1 antibody (αmTfR1)-PMO conjugates: cleavable and noncleavable linkers, linker location on the PMO, and the impact of drug-to-antibody ratios (DARs) on plasma pharmacokinetics (PK), oligonucleotide delivery to tissues, and exon skipping. AOCs containing a stable linker with a DAR9.7 were the most effective PMO delivery vehicles in preclinical studies. We demonstrate that αmTfR1-PMO conjugates induce dystrophin protein restoration in the skeletal and heart muscles of mdx mice. Our results show that αmTfR1-PMO conjugates are a potentially effective approach for the treatment of DMD.
- Published
- 2024
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