| Autor: |
Binz HK; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Bakker TR; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Phillips DJ; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Cornelius A; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Zitt C; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Göttler T; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Sigrist G; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Fiedler U; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Ekawardhani S; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Dolado I; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Saliba JA; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Tresch G; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Proba K; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland., Stumpp MT; a Molecular Partners AG , Wagistrasse 14, Schlieren , Switzerland. |
| Abstrakt: |
MP0250 is a multi-domain drug candidate currently being tested in clinical trials for the treatment of cancer. It comprises one anti-vascular endothelial growth factor-A (VEGF-A), one anti-hepatocyte growth factor (HGF), and two anti-human serum albumin (HSA) DARPin® domains within a single polypeptide chain. While there is first clinical validation of a single-domain DARPin® drug candidate, little is known about DARPin® drug candidates comprising multiple domains. Here, we show that MP0250 can be expressed at 15 g/L in soluble form in E. coli high cell-density fermentation, it is stable in soluble/frozen formulation for 2 years as assessed by reverse phase HPLC, it has picomolar potency in inhibiting VEGF-A and HGF in ELISA and cellular assays, and its domains are simultaneously active as shown by surface plasmon resonance. The inclusion of HSA-binding DARPin® domains leads to a favorable pharmacokinetic profile in mouse and cynomolgus monkey, with terminal half-lives of ∼ 30 hours in mouse and ∼ 5 days in cynomolgus monkey. MP0250 is thus a highly potent drug candidate that could be particularly useful in oncology. Beyond MP0250, the properties of MP0250 indicate that multi-domain DARPin® proteins can be valuable next-generation drug candidates. |
