Design and characterization of MP0250, a tri-specific anti-HGF/anti-VEGF DARPin® drug candidate.

Abstract

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.

• Authors: H Kaspar Binz, Talitha R Bakker, Douglas J Phillips, Andreas Cornelius, Christof Zitt, Thomas Göttler, Gabriel Sigrist, Ulrike Fiedler, Savira Ekawardhani, Ignacio Dolado, Johan Abram Saliba, Gaby Tresch, Karl Proba, Michael T Stumpp
• Journal: mAbs (MAbs) 2017 Nov/Dec Vol. 9 Issue 8 Pg. 1262-1269 ISSN: 1942-0870 [Electronic] United States
• PMID: 29035637 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• HGF protein, human
• MP0250
• Recombinant Fusion Proteins
• Vascular Endothelial Growth Factor A
• Hepatocyte Growth Factor
• Serum Albumin, Human

Topics

• Administration, Intravenous
• Animals
• Ankyrin Repeat (genetics, immunology)
• Antibodies, Monoclonal (administration & dosage, immunology, pharmacokinetics)
• Antibody Specificity (immunology)
• Antineoplastic Agents (administration & dosage, immunology, pharmacokinetics)
• Drug Design
• Female
• Half-Life
• Hepatocyte Growth Factor (antagonists & inhibitors, genetics, immunology)
• Humans
• Infusions, Intravenous
• Macaca fascicularis
• Male
• Mice, Inbred BALB C
• Protein Binding (immunology)
• Recombinant Fusion Proteins (administration & dosage, genetics, immunology, metabolism, pharmacokinetics)
• Serum Albumin, Human (genetics, immunology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, genetics, immunology)