Design and characterization of MP0250, a tri-specific anti-HGF/anti-VEGF DARPin® drug candidate. Issue 8 (17th November 2017)

• Record Type: Journal Article
• Authors: Binz, H. Kaspar; Bakker, Talitha R.; Phillips, Douglas J.; Cornelius, Andreas; Zitt, Christof; Göttler, Thomas; Sigrist, Gabriel; Fiedler, Ulrike; Ekawardhani, Savira; Dolado, Ignacio; Saliba, Johan Abram; Tresch, Gaby; Proba, Karl; Stumpp, Michael T.
• Is Part Of: MAbs. Volume 9:Issue 8(2017)
• Page Start: 1262
• Page End: 1269
• Publication Date: 2017-11-17
• Subjects: DARPin® -- HGF -- multi-specificity -- pharmacokinetics -- serum albumin -- VEGF; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2017.1305529
• Languages: English
• ISSNs: 1942-0862

Abstract

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.