title: Immune suppression in cynomolgus monkeys by XPro9523: an improved CTLA4-Ig fusion with enhanced binding to CD80, CD86 and neonatal Fc receptor FcRn.
abstract: The CTLA4-Ig fusion proteins abatacept and belatacept are clinically proven immunosuppressants used for rheumatoid arthritis and renal transplant, respectively. Given that both biologics are typically administered chronically by infusion, a need exists for a next-generation CTLA4-Ig with more convenient dosing. We used structure-based protein engineering to optimize the affinity of existing CTLA4-Ig therapeutics for the ligands CD80 and CD86, and for the neonatal Fc receptor, FcRn. From a rationally designed library, we identified four substitutions that enhanced binding to human CD80 and CD86. Coupled with two IgG1 Fc substitutions that enhanced binding to human FcRn, these changes comprise the novel CTLA4-Ig fusion protein, XPro9523. Compared with abatacept, XPro9523 demonstrated 5.9-fold, 23-fold, and 12-fold increased binding to CD80, CD86, and FcRn, respectively; compared with belatacept, CD80, CD86, and FcRn binding increased 1.5-fold, 7.7-fold, and 11-fold, respectively. XPro9523 and belatacept suppressed human T cell proliferation and IL-2 production more potently than abatacept. XPro9523 also suppressed inflammation in the mouse collagen-induced arthritis model. In cynomolgus monkeys, XPro9523 saturated CD80 and CD86 more effectively than abatacept and belatacept, potently inhibited IgM and IgG immunization responses, and demonstrated longer half-life. Pharmacokinetic modeling of its increased potency and persistence suggests that, in humans, XPro9523 may demonstrate superior efficacy and dosing convenience compared with abatacept and belatacept.
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bernett
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Seung Y
authors.initials: SY
authors.lastname: Chu
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Leung
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Moore
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Sung-Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Pong
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Hsing
authors.initials: H
authors.lastname: Chen
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Phung
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Umesh S
authors.initials: US
authors.lastname: Muchhal
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Horton
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Lazar
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Desjarlais
authors.affiliation: Xencor, Inc.; Monrovia, CA USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Szymkowski
mesh_terms: D000069594:Abatacept; D000818:Animals; D000915:Antibody Affinity; D000917:Antibody Formation / Q000187:drug effects; D001169:Arthritis, Experimental / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006084:Graft Rejection / Q000628:therapy*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects* / Q000276:immunology; D015202:Protein Engineering; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015395:Histocompatibility Antigens Class I; D018796:Immunoconjugates; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; C100688:Fc receptor, neonatal
keywords: Abatacept; CD80; CD86; CTLA4-Ig; Fc engineering; FcRn; belatacept; biosuperior; rheumatoid arthritis; transplantation
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