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

被引：6

作者：

Oshima, Shinsuke ^{[1
]}

Karrer, Erik E. ^{[2
]}

Paidhungat, Madan M. ^{[2
]}

Neighbors, Margaret ^{[3
]}

Chapin, Steven J. ^{[3
]}

Fan, Rong A. ^{[3
]}

Reed, Margaret A. ^{[3
]}

Wu, Kuoting ^{[3
]}

Wong, Clifford ^{[3
]}

Chen, Yonghong ^{[5
]}

Whitlow, Marc ^{[4
]}

Anderson, Francisco A. ^{[2
]}

Bam, Rujuta A. ^{[2
]}

Zhang, Qian ^{[2
]}

Larsen, Brent R. ^{[5
]}

Viswanathan, Sridhar ^{[6
]}

Devens, Bruce H. ^{[3
]}

Bass, Steven H. ^{[2
]}

Higashi, Yasuyuki ^{[1
]}

机构：

[1] Astellas Pharma Inc, Pharmacol Res Labs, Drug Discovery Res, Tsukuba, Ibaraki 3058585, Japan

[2] Perseid Therapeut, Dept Mol Biol, Redwood City, CA 94063 USA

[3] Perseid Therapeut, Dept Biol & Pharmacol, Redwood City, CA 94063 USA

[4] Colabrativ Inc, Orinda, CA 94563 USA

[5] Perseid Therapeut, Dept Prot Analyt & Pharmaceut, Redwood City, CA 94063 USA

[6] Perseid Therapeut, Dept Proc Dev & Mfg, Redwood City, CA 94063 USA

来源：

PROTEIN ENGINEERING DESIGN & SELECTION | 2016年 / 29卷 / 05期

关键词：

costimulation blockade; next-generation protein therapeutics; phage display; rheumatoid arthritis; transplantation; COSTIMULATION BLOCKADE; B-CELL; CTLA-4; CD28; GENE; TRANSPLANTATION; BELATACEPT; ACTIVATION; EXPRESSION; RESPONSES;

D O I：

10.1093/protein/gzw002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：159 / 167

页数：9

共 2 条

[1] Immunosuppressive effect of ASP2408, a novel CD86-selective variant of CTLA4-Ig, in rats and cynomolgus monkeys
Oshima, Shinsuke
Fujii, Yasutomo
Karrer, Erik E.
Takamura, Fujiko
Chapin, Steven J.
Neighbors, Margaret
Viswanathan, Sridhar
Devens, Bruce H.
Higashi, Yasuyuki
Mizuhara, Hidekazu
INTERNATIONAL IMMUNOPHARMACOLOGY, 2016, 40 : 310 - 317
[2] The Effect of ASP2409, a Novel CD86-Selective Variant of CTLA4-Ig, on Renal Allograft Rejection in Nonhuman Primates
Oshima, Shinsuke
Karrer, Erik E.
Kawato, Yuka
Maeda, Masashi
Fukahori, Hidehiko
Tsujimoto, Susumu
Hirose, Jun
Nakamura, Koji
Marui, Takanori
Takamura, Fujiko
Noto, Takahisa
Chapin, Steven J.
Fujii, Yasutomo
Neighbors, Margaret
Viswanathan, Sridhar
Devens, Bruce H.
Higashi, Yasuyuki
TRANSPLANTATION, 2016, 100 (12) : 2611 - 2620

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