Macromolecules: Conjugate of saponin, oligonucleotide and galnac

I’m Helmus van de Langemheen, Senior Scientist and project manager at Symeres. I have been involved with this project from the start, which began in late 2018.

Sapreme is developing improved macromolecule delivery mechanisms by circumventing endosomal entrapment. For this, they work with the endosomal escape enhancer SPT001. This large molecule is a derivative of a natural compound found in soapwort.

The ENDOSCAPE® platform from Sapreme is based on SPT001-containing compounds, which can release trapped cargo from the endolysosomal membranes, improving the therapeutic window and enabling access to intracellular targets with minimal toxicity. By conjugating this molecule to antibody- or small-molecule-targeting ligands and intracellularly active proteins or oligonucleotides, Sapreme aims to enhance intracellular target engagement and improve therapeutic efficacy without limitation to biological modality or indication.

Since SPT001 is most active in its released form, we designed and developed cleavable linkers as well as dendron systems containing as many as eight cleavable SPT001 molecules. Moreover, by using smart conjugation strategies, we combined these constructs with cleavable antisense oligonucleotides (ASOs) and a liver-targeting trivalent GalNAc. By doing so, conjugates with a molecular weight up to 40 kDa were prepared.

Until January of this year, I worked on the project myself. By then, Sapreme saw so much potential that they asked us to expand the FTE team, so Maarten de Bruijn and Frederique Turlings joined me.

In general, just working with these very large molecules was a great challenge, as it’s a whole different ball game compared with normal small-molecule synthesis. In particular, the purification and analysis of these compounds is far from straightforward.

Being able to help Sapreme with building their ENDOSCAPE® platform and by doing so, hopefully in the end, make a real difference to the future of macromolecule therapies.