ASP2408 and ASP2409, novel CTLA4-Ig variants with CD86-selective ligand binding activity and improved immunosuppressive potency, created by directed evolution

Abstract 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 met...

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Bibliographic Details
Published in:Protein engineering, design and selection design and selection, 2016-05, Vol.29 (5), p.159-167
Main Authors: Oshima, Shinsuke, Karrer, Erik E., Paidhungat, Madan M., Neighbors, Margaret, Chapin, Steven J., Fan, Rong A., Reed, Margaret A., Wu, Kuoting, Wong, Clifford, Chen, Yonghong, Whitlow, Marc, Anderson, Francisco A., Bam, Rujuta A., Zhang, Qian, Larsen, Brent R., Viswanathan, Sridhar, Devens, Bruce H., Bass, Steven H., Higashi, Yasuyuki
Format: Article
Language:English
Subjects:
Abatacept - chemistry
Abatacept - genetics
Abatacept - metabolism
Abatacept - pharmacology
Amino Acid Sequence
Animals
B7-2 Antigen - metabolism
Cercopithecus aethiops
COS Cells
Directed Molecular Evolution
Female
Humans
Immunoconjugates - chemistry
Immunoconjugates - metabolism
Immunoconjugates - pharmacology
Immunosuppressive Agents - chemistry
Immunosuppressive Agents - metabolism
Immunosuppressive Agents - pharmacology
Ligands
Mice
Models, Molecular
Protein Conformation
Substrate Specificity
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Summary:Abstract 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 potency in vitro and in 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.
ISSN:1741-0126
1741-0134
DOI:10.1093/protein/gzw002