Immunosuppressive effect of ASP2408, a novel CD86-selective variant of CTLA4-Ig, in rats and cynomolgus monkeys.
The CTLA4-Ig fusion proteins abatacept and belatacept inhibit CD28-mediated T cell activation by binding CD80 (B7-1) and CD86 (B7-2) costimulatory ligands and are clinically proven immunosuppressants used for rheumatoid arthritis and renal transplantation, respectively. Abatacept and belatacept preferentially bind CD80, yet CD86 has been implicated as the dominant ligand for CD28-mediated costimulation of T cells. We investigated the immunosuppressive effects of ASP2408, a novel CTLA4-Ig with CD86 selectivity and high potency created by directed evolution methods. Here we evaluated the effect of ASP2408 in vitro using cynomolgus monkey and rat T cell proliferation assays and in vivo using cynomolgus monkey tetanus toxoid (TTx) immunization and a rat rheumatoid arthritis model. ASP2408 was 290-fold and 21-fold more potent in suppressing in vitro monkey T cell proliferation than abatacept and belatacept, respectively. ASP2408 inhibited anti-TTx immunological reactions in cynomolgus monkey at a 10-fold lower dose level than belatacept, through complete CD86 and partial CD80 receptor occupancies, and also suppressed inflammation in the rat collagen-induced arthritis model. Overall, improved immunosuppressive potency of ASP2408 relative to abatacept and belatacept correlated well with improved CD86 binding affinity. These results may support the advantage of preferential enhancement of CD86 binding affinity to inhibit T cell-mediated immune response and improved dosing convenience in humans relative to abatacept or belatacept.
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 3058585, Japan. Electronic address: shinsuke.ooshima@astellas.com.
Shinsuke
S
Oshima
Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 3058585, Japan.
Yasutomo
Y
Fujii
Department of Molecular Biology, Perseid Therapeutics, Redwood City, CA 94063, USA.
Erik E
EE
Karrer
Pharmacokinetics-Pharmacodynamics Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 3058585, Japan.
Fujiko
F
Takamura
Department of Biology and Pharmacology, Perseid Therapeutics, Redwood City, CA 94063, USA.
Steven J
SJ
Chapin
Department of Biology and Pharmacology, Perseid Therapeutics, Redwood City, CA 94063, USA.
Margaret
M
Neighbors
Department of Process Development and Manufacturing, Perseid Therapeutics, Redwood City, CA 94063, USA.
Sridhar
S
Viswanathan
Department of Biology and Pharmacology, Perseid Therapeutics, Redwood City, CA 94063, USA.
Bruce H
BH
Devens
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 3058585, Japan.
Yasuyuki
Y
Higashi
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 3058585, Japan.
Hidekazu
H
Mizuhara
D000069594:Abatacept / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000473:pathology; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D024043:Collagen Type II / Q000276:immunology; D005260:Female; D005528:Foot / Q000473:pathology; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects; D013745:Tetanus Toxoid / Q000276:immunology
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D024043:Collagen Type II; D007166:Immunosuppressive Agents; D013745:Tetanus Toxoid; D000069594:Abatacept
ASP2408; CD86; CTLA4-Ig; Next-generation protein therapeutics; Non-human primate; Rheumatoid arthritis