Antibody-oligonucleotide conjugate

Antibody-oligonucleotide conjugates or AOCs belong to a class of chimeric molecules combining in their structure two important families of biomolecules: monoclonal antibodies and oligonucleotides.

The first AOC was reported in 1995 where the lysines of a transferrin-antibody were connected using a SMCC bifunctional linker (NHS ester and maleimide moiety) to radiolabelled and cys-bearing ASOs targeting HIV mRNA.

[5] In 2013, MYERS and coworkers then unspecifically labelled an anti-CD19 antibody with N-succinimidyl 3-(2-pyridyl-dithio) propionate to form disulphide bonds with cys-modified ASO targeting the mRNA of oncoprotein E2A–PBX1.

[11] The main obstacle encountered was a limited endosomal escape but ultimately a functional construct which shows antisense effect in-vivo was reported.

[14][15][16] Despite their tremendous potential, ADCs and AOCs suffer from the physical size of the antibody (mAb) entity (150 kDa) which limits solid tumour penetration (at least at low concentrations).

Moreover, the site-selective modification of the antibody is hardly achievable: due to the difficult production of mAbs the selective introduction of an unnatural amino acid into the protein is not easily possible.