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August 13, 2026Journal of Medicinal Chemistry

Neutral BackboneModifications Enhance the Pharmacokineticsand Biodistribution of Antibody–Oligonucleotide Conjugateswith High Drug-to-Antibody Ratios

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Overview

Randomized trial demonstrates improved pharmacokinetics in mice with modified antibody-oligonucleotide conjugates, suggesting therapeutic advancements.

Key Points

  • This research aims to enhance the pharmacokinetics and biodistribution of antibody-oligonucleotide conjugates by modifying their chemical structure.
  • Investigated siRNA modifications to reduce charge and phosphorothioate content.
  • Utilized neutral backbone chemistries including phosphoryl guanidine, methoxypropylphosphonate, and triester linkages in AOCs.
  • Conducted pharmacokinetic and biodistribution assessments in mice.
  • PG-modified DAR2 AOCs showed improved pharmacokinetics compared to unmodified conjugates with reduced muscle delivery.
  • Achieved enhanced tissue distribution in the liver with maintained siRNA activity.
  • Results support optimization pathways for high-drug-to-antibody ratio conjugates.

Cite This Study

A 2026 study studied this question.

synapsesocial.com/papers/6a7d76062b0e0cff3f63f1d3https://doi.org/10.1021/acs.jmedchem.6c00565
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