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

被引:49
作者
Binz, H. Kaspar [1 ]
Bakker, Talitha R. [1 ]
Phillips, Douglas J. [1 ]
Cornelius, Andreas [1 ]
Zitt, Christof [1 ]
Gottler, Thomas [1 ]
Sigrist, Gabriel [1 ]
Fiedler, Ulrike [1 ]
Ekawardhani, Savira [1 ]
Dolado, Ignacio [1 ]
Saliba, Johan Abram [1 ]
Tresch, Gaby [1 ]
Proba, Karl [1 ]
Stumpp, Michael T. [1 ]
机构
[1] Mol Partners AG, Wagistr 14, CH-8952 Schlieren, Switzerland
关键词
DARPin (R); HGF; multi-specificity; pharmacokinetics; serum albumin; VEGF; DISPLAYS CYTOTOXIC ACTIVITY; MONOCLONAL-ANTIBODY; PROSTATE-CANCER; REPEAT PROTEINS; LUNG-CANCER; PHASE-II; MET; CABOZANTINIB; ONARTUZUMAB; PHARMACOKINETICS;
D O I
10.1080/19420862.2017.1305529
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 (R) domains within a single polypeptide chain. While there is first clinical validation of a single-domain DARPin (R) drug candidate, little is known about DARPin (R) drug candidates comprising multiple domains. Here, we show that MP0250 can be expressed at 15g/L in soluble form in E. coli high cell-density fermentation, it is stable in soluble/frozen formulation for 2years 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 (R) domains leads to a favorable pharmacokinetic profile in mouse and cynomolgus monkey, with terminal half-lives of similar to 30 hours in mouse and similar to 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 (R) proteins can be valuable next-generation drug candidates.
引用
收藏
页码:1262 / 1269
页数:8
相关论文
共 34 条
[1]   Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET [J].
Basilico, Cristina ;
Pennacchietti, Selma ;
Vigna, Elisa ;
Chiriaco, Cristina ;
Arena, Sabrina ;
Bardelli, Alberto ;
Valdembri, Donatella ;
Serini, Guido ;
Michieli, Paolo .
CLINICAL CANCER RESEARCH, 2013, 19 (09) :2381-2392
[2]   Incidence and risk of hand-foot skin reaction with cabozantinib, a novel multikinase inhibitor: a meta-analysis [J].
Belum, V. R. ;
Serna-Tamayo, C. ;
Wu, S. ;
Lacouture, M. E. .
CLINICAL AND EXPERIMENTAL DERMATOLOGY, 2016, 41 (01) :8-15
[3]   High-affinity binders selected from designed ankyrin repeat protein libraries [J].
Binz, HK ;
Amstutz, P ;
Kohl, A ;
Stumpp, MT ;
Briand, C ;
Forrer, P ;
Grütter, MG ;
Plückthun, A .
NATURE BIOTECHNOLOGY, 2004, 22 (05) :575-582
[4]   Engineering novel binding proteins from nonimmunoglobulin domains [J].
Binz, HK ;
Amstutz, P ;
Plückthun, A .
NATURE BIOTECHNOLOGY, 2005, 23 (10) :1257-1268
[5]   Designing repeat proteins:: Well-expressed, soluble and stable proteins from combinatorial libraries of consensus ankyrin repeat proteins [J].
Binz, HK ;
Stumpp, MT ;
Forrer, P ;
Amstutz, P ;
Plückthun, A .
JOURNAL OF MOLECULAR BIOLOGY, 2003, 332 (02) :489-503
[6]   Receptor tyrosine kinase inhibitors in thyroid cancer [J].
Castellone, Maria Domenica ;
Carlomagno, Francesca ;
Salvatore, Giuliana ;
Santoro, Massimo .
BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM, 2008, 22 (06) :1023-1038
[7]   Drug development of MET inhibitors: targeting oncogene addiction and expedience [J].
Comoglio, Paolo M. ;
Giordano, Silvia ;
Trusolino, Livio .
NATURE REVIEWS DRUG DISCOVERY, 2008, 7 (06) :504-516
[8]   False-negative rate for HER2 testing in 738 gastric and gastroesophageal junction cancers (GEC) from two global randomized clinical trials [J].
Cunningham, David ;
Shah, Manish A. ;
Smith, Dustin ;
Zoudilova, Maria ;
Hack, Stephen Paul ;
Kang, Alice ;
Phan, See-Chun ;
Jubb, Adrian M. ;
Ruschoff, Josef .
JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (03)
[9]  
Escudier Bernard, 2007, Clin Adv Hematol Oncol, V5, P530
[10]   Angiogenesis as a therapeutic target [J].
Ferrara, N ;
Kerbel, RS .
NATURE, 2005, 438 (7070) :967-974