On September 23, 2020 Sapreme, a biotechnology company focused on improving the delivery and efficacy of macromolecule therapeutics, reported positive preclinical data on its proprietary endosomal escape platform in two presentations at the 16th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held virtually from September 27th to 30th, 2020 (Press release, Sapreme Technologies, SEP 28, 2020, View Source [SID1234567684]).

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Sapreme is developing macromolecule delivery methods based on compounds that release therapeutic cargo from the endo-lysosome, improving access to intracellular targets and enhancing the therapeutic window for these therapeutics. Current macromolecular biologics rely on receptor-mediated endocytic uptake into the endosome and inefficient passive release from these vesicles into the cell to achieve therapeutic efficacy. The company’s presentations demonstrate that Sapreme’s SPT001 compound improves intracellular release of targeted antisense oligonucleotides (ASOs) and thereby also their therapeutic efficacy. In addition to ASOs, SPT001 has also been demonstrated to enhance delivery of other targeted payloads such as antibody-conjugated toxins.

"The data presented today underscore the broad potential of our platform to overcome endosomal entrapment and improve the therapeutic window of macromolecule therapeutics," stated Guy Hermans, Ph.D., Chief Executive Officer of Sapreme. "We are encouraged to see that conjugating SPT001 to liver or tumor targeted ASOs leads to significantly improved silencing, with positive implications for development of metabolic syndrome and oncology targeting drug developments. These results support the further development of SPT001 as the delivery mechanism of choice for future intracellularly active macromolecular drug candidates."

As described in the presentations, multiple in vitro preclinical studies were conducted demonstrating the broad potential of SPT001. Highlights from the data include:

In one experiment, an ASO targeting HSP27 was tested separately or conjugated to monoclonal antibody (mAb) Cetuximab, an epidermal growth factor receptor (EGFR) targeting antibody. While antibody targeting slightly improved HSP27 silencing, results from the study demonstrated that the additional conjugation of SPT001 to the ASO-mAb compound resulted in a highly improved and target-dependent reduction of HSP27 expression.
Further studies showed that combining Cetuximab-SPT001 with Cetuximab-ASO conjugates similarly improved ASO delivery efficacy – demonstrating SPT001 can also improve delivery of an ASO not directly linked to it. Also, combined treatment by Cetuximab-SPT001 and Trastuzumab-ASO of EGFR/Her2 double positive cells yields similar synergies. This dual targeting approach allows for the introduction of additional tumor cell selectivity. Furthermore, such combined Trastuzumab-ASO delivery was effective in double positive cells expressing only low levels of Her2, which are typically not sensitive to Trastuzumab-ASO in the absence of SPT001.
In a third study, Sapreme evaluated the effect of using SPT001 conjugates to improve oligonucleotide delivery to liver cells. N-Acetylgalactosamine (GalNAc) is used as a targeting ligand to drive liver uptake of many oligonucleotides in many late stage clinical trials. ApoB overexpression is known to result in lipid-induced endoplasmic reticulum stress and insulin resistance in the liver, and efficient silencing of ApoB is therefore of therapeutic interest. High doses of GalNAc-ApoB silencing ASOs were required to reduce ApoB expression, whereas combination treatment with GalNAc conjugated SPT001 allowed for complete gene silencing at considerably reduced doses. Similarly, combining SPT001 and ASO payloads with GalNAc into a single next generation compound, resulted in a molecule of superior potency as compared to the GalNAc-ApoB benchmark. Reduced ApoB protein production levels confirmed mRNA silencing results, demonstrating SPT001 conjugates can improve on existing compounds in combination therapy, or serve as building blocks for next generation drug candidates.
The presentations are available on demand at the 16th Annual Meeting of the OTS conference website through this link.