Antibody-siRNA Conjugates

Antibody-siRNA ConjugatesMechanistically, antibody-siRNA conjugates (ARCs) exert their activity by

Specific binding of antibody to target

Internalization

Degradation and release the siRNA

Reducing the gene expression

The main advantage of ARCs is high ligand binding efficiency and prolonged presence in blood due to high molecular weight (~150 kDa). However, the development of ARC is still at the early stage. Though the design principle of ARC is somewhat the same with ADC, there are still some challenges for ARC:

Difficult to internalize due to high polarity of RNA.

Immune response.

Difficult to bind the antigen with high expression in target tissue.

Efficiency of internalization.

Selectivity: antibody mediated internalization is not the only endocytosis pathway, which leads to low selectivity.

Technical obstacles on scale up production and purification.

Thus, further optimization, including the use of humanized antibodies or Fab fragments, endosomolytic agents, and chemically-modified siRNAs, are potential strategies for the use of ARCs in the clinic.