Protein Life Extension Using Glycosylation Rich Sequences


The National Institute for Biotechnology
in the Negev Ltd.
Ben-Gurion University of the Negev



With a growing number of protein therapeutics being developed, many of them exhibiting a short plasma half-life, extension of protein’s half-life is of paramount importance as it can help to reduce the number of applications, to lower drug doses, thus bringing therapeutic and economic benefits. One example of such a protein is the human Growth Hormone (hGH) which has been the subject of several technologies, all aiming for long-acting hGH formulations. Current therapeutic regimens rely on daily subcutaneous rhGH injections that are inconvenient, painful, and distressing for patients, children in particular, often leading to noncompliance and reduced effectiveness. We aimed to develop a long-acting rhGH formulation with increased half-life and stability and thus to reduce the number of injections needed.  Another example is the cytokine IL-2 omitted from clinical treatment due to high toxicity. We aimed to develop life-extended IL-2 that could be injected in low concentrations maintaining efficacy while reducing toxicity.


The Technology


We introduced a proprietary human amino acid sequence(s) that upon conjugation (at the DNA level), is able to enhance the in-vivo drug life of a soluble protein drugs while maintaining their biological activity. SPA and APE sequences are specific human sequences reach in O-glycosylation. We showed that rHCGβ in which the C-terminal peptide (CTP) sequence was replaced by SPA-APE had significantly better T1/2 as compared to wt rHCGβ with its CTP. Our modified rhGH chimeric protein, contain within its sequence the SPA moiety, which supports its prolonged systemic presence. The modified rhGH achieved biological activity on a weekly basis rather than daily regimen. These results are comparable which those of the competing GH products in clinical development. Importantly, we are using rhGH as a technological proof of concept for other relevant proteins including hIL-2, which we shownto have better efficacy in vivo




  • SPA-APE modified rHCGβ had significantly higher T1/2 as compared to wt rHCGβ with CTP
  • SPA-modified rhGH, in which SPA was introduced within the GH, demonstrated significantly higher half-life in vivo, induce significant gain weight of Hypophysectomized rats on a weekly-based treatment in contrast to clinical-grade GH, and manifested slow release from subcutaneous injection.
  • We studied whether the SPA introduced within the GH in a specific site is enzymatically removed upon GH binding to target cells; If proven then this modification could be considered (regulatory-based) as vehicle to enhance GH activity rather than as a modified GH.
  • The rhGH product is being jointly developed with an international CMO
  • SPA-APE modified IL-2 manifested better activity in vitro and significantly higher T1/2 in vivo as compared to clinical grade IL-2 (proleukin), while activating T and NK.
  • The technology could be applied to other short-live soluble cytokines, short-live storage enzymes related to storage diseases, short live soluble ligands (Like GLP1), hormones (like GH) protein-type co-factors (like factors 7 and 9 in the coagulation system, ScFv-based drugs (within the linker of the Vl-Vh) and antibodies (conjugated to the HC-CH3 or Cl).


Patent Status


PCT patent application No. PCT/IL2017/050788, filed July 11, 2017
National phase entry in: Australia, China, Canada, Israel, Europe, Hong Kong and USA


Principal Investigator


Prof. Angel Porgador; NIBN and the Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.