ASP2408 and ASP2409, novel CTLA4-Ig variants with CD86-selective ligand binding activity and improved immunosuppressive potency, created by directed evolution
| Autor: | Kuoting Wu, Clifford Wong, Margaret Neighbors, Erik E. Karrer, Yasuyuki Higashi, Madan M. Paidhungat, Steven J. Chapin, Steven H. Bass, Bruce H. Devens, Shinsuke Oshima, Margaret Reed, Brent R. Larsen, Yonghong Chen, Francisco A. Anderson, Marc Whitlow, Rujuta A. Bam, Sridhar Viswanathan, Rong A. Fan, Qian Zhang |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Immunoconjugates Protein Conformation chemical and pharmacologic phenomena Bioengineering Pharmacology Ligands Biochemistry Belatacept Substrate Specificity Abatacept Mice 03 medical and health sciences 0302 clinical medicine Chlorocebus aethiops medicine Animals Humans Potency Amino Acid Sequence Molecular Biology CD86 Chemistry hemic and immune systems Protein engineering Directed evolution Ligand (biochemistry) Transplantation 030104 developmental biology COS Cells Female B7-2 Antigen Directed Molecular Evolution Immunosuppressive Agents CD80 030215 immunology Biotechnology medicine.drug |
| Zdroj: | Protein Engineering Design and Selection. 29:159-167 |
| ISSN: | 1741-0134 1741-0126 |
| DOI: | 10.1093/protein/gzw002 |
| Popis: | The CTLA4-Ig therapeutics abatacept and belatacept inhibit CD28-mediated T cell activation by binding CD80 (B7-1) and CD86 (B7-2) co-stimulatory ligands. Both compounds preferentially bind CD80, yet CD86 has been implicated as the dominant co-stimulatory ligand. Using directed evolution methods, novel CTLA4-Ig variants were created with selective CD86 binding affinity, a property that confers increased immunosuppressive potency and potentially improved efficacy and safety profiles. Relative to abatacept (wild-type CTLA4-Ig), ASP2408 and ASP2409 have 83-fold and 220-fold enhanced binding affinity to CD86 while retaining 1.5-fold and 5.6-fold enhanced binding affinity to CD80, respectively. Improvements in CD86 binding affinity correlates with increased immunosuppressive potencyin vitroandin vivo Our results highlight the power of directed evolution methods to obtain non-intuitive protein engineering solutions and represent the first examples of CD86-selective CTLA4-Ig compounds that have entered clinical trials. |
| Databáze: | OpenAIRE |
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