SAPA-NE 2022 Bimonthly Workshop

Efficient on-target delivery of oligonucleotides (and beyond): in vitro and in vivo performance of Sapreme’s endosomal escape enhancers for various tissues and targets

Keypoints

· Sapreme’s endosomal escape enhancers optimize cytoplasmic release to reveal full efficacy

· Delivery of oligonucleotides and protein therapeutics with broad applicability

· Targeting through ligand-conjugation to increase cell/tissue-specificity

Abstract

For most current therapeutic oligonucleotide formats, attaining sufficiently high levels of cytoplasmic or nuclear target engagement while keeping off-target toxicities at bay remains problematic, as most compound remains trapped in the endosomes. Sapreme’s technologies allow for highly relevant improvements in potency by enabling efficient endosomal escape. Moreover, it allows for exquisite tissue- or cell selective targeting through the use of targeting ligands, including GalNAc for hepatic targeting, and antibodies or other ligands for non-hepatic tissues.

Here, we will present select in vitro and in vivo data to illustrate the versatility and general applicability of Sapreme’s endosomal escape technologies for different tissues and targets. Specifically, we will show data to support that in vivo gene expression knock-down achieved with Sapreme’s endosomal escape technology occurs at substantially reduced oligonucleotide doses, for example in the liver. Furthermore, we will share data showing longer term persistence of relevant downstream biomarkers, demonstrating improved cytoplasmic delivery does not preclude convenient dosing schedules. Combined with a benign tox profile, this supports an attractive developability profile. Lastly, we will highlight how such concepts translate to extrahepatic tissue targeting for diverse payloads, including oligonucleotides and protein payloads, to illustrate the general applicability of Sapreme’s platform.

Speaker

Miriam Bujny, PhD, Chief Dev. Officer, SapremeTechnologies BV

Dr Miriam Bujny joined Sapreme as CDO in 2020. She is an experienced translational science lead with background in RNA and antibody therapeutics, and uses this background at Sapreme to drive the development of next-generation macromolecules that circumvent endosomal entrapment.

Over the last twelve years, Miriam has held leadership positions in various drug discovery and early clinical development roles. At ProQR Therapeutics, she headed the Translational Science department with early development activities for several RNA therapy programs. Most recently, as Senior Director R&D at ProQR, she served as project leader responsible to lead an oligonucleotide candidate for a front-of-eye indication from research into the clinic. From 2012 to 2016, she worked in various roles for The Janssen Pharmaceutical companies of Johnson&Johnson, including anti-viral antibody therapy development and as Principal Scientist Predictive Biomarkers. From 2010 to 2012, Miriam worked as Scientist at Crucell, before its acquisition by Johnson & Johnson, in the Innovation & Discovery Labs on therapeutic antibody discovery. Miriam holds a Ph.D. in biochemistry from the University of Bristol with a specialization in endosomal transport. She completed postdoctoral training in the lab of Dr. Xiaowei Zhuang at Harvard University.