Genetic Polymorphisme of FCGRT Encoding FcRn in a Japanese Population and Their Functional Analysis

Ishii‐Watabe, Akiko; Saito, Yoshiro; Suzuki, Tomoya; Tada, Minoru; Ukaji, Maho; Maekawa, Keiko; Kurose, Kouichi; Kaniwa, Nahoko; Sawada, Jun Ichi; Kawasaki, Nana; Yamaguchi, Teruhide; Nakajima, Takako Eguchi; Kato, Ken; Yamada, Yasuhide; Shimada, Yasuhiro; Yoshida, Teruhiko; Umemura, Takashi; Saito, Mizuki; Muro, Kei; Doi, Toshihiko; Fuse, Nozomu; Yoshino, Takayuki; Ohtsu, Atsushi; Saijo, Nagahiro; Hamaguchi, Tetsuya; Okuda, Haruhiro; Matsumura, Yasuhiro

doi:10.2133/dmpk.dmpk-10-rg-067

Cited by 19 publications

(11 citation statements)

References 23 publications

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“…There were no unique treatment-related adverse events reported in Japanese subjects, and no inhibitors were detected. nese subjects and in other ethnic groups [21][22][23][24] ; however, no functional differences in FcRn due to these polymorphisms were observed, 22 consistent with the similar pharmacokinetic profiles observed. Japanese and non-Japanese subjects in B-LONG was not prespecified, and thus this was a post hoc analysis.…”

Section: Discussionsupporting

confidence: 73%

Japanese subject subpopulation analysis of B-LONG: a Phase 3 study of long-acting recombinant factor IX Fc fusion protein

Shima

Fukutake

Hanabusa

et al. 2015

Nihon Kessen Shiketsu Gakkaishi

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Abstract:The multinational Phase 3 B-LONG study demonstrated the prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) versus native recombinant factor IX (rFIX), and the safety and efficacy of rFIXFc for treatment of bleeding and routine prophylaxis in subjects with hemophilia B. This post hoc subgroup analysis of B-LONG evaluated the safety, efficacy, and pharmacokinetics of rFIXFc in Japanese subjects. Previously treated males with moderately severe to severe hemophilia B (endogenous FIX ≤2 IU/dL) received weekly prophylaxis (starting at 50 IU/kg/week, with dose adjustment), individualized interval prophylaxis (starting at 100 IU/kg every 10 days, with interval adjustment), episodic treatment, or perioperative management with rFIXFc. Primary endpoints were annualized bleeding rates (ABRs) and safety. rFIXFc pharmacokinetics were comparable between Japanese subjects (n=6) and non-Japanese subjects. Median ABRs for Japanese subjects in the weekly prophylaxis (n=4) and individualized interval prophylaxis (n=2) groups were 3.27 and 4.28, respectively, which were within the range for non-Japanese subjects. For Japanese subjects, most (95.8%) bleeding episodes were resolved with 1 or 2 rFIXFc infusions, and no treatment-related adverse events or inhibitors were observed. rFIXFc was safe and efficacious for prophylaxis and treatment of bleeding in Japanese subjects with outcomes and pharmacokinetics comparable to non-Japanese subjects.

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Section: Discussionsupporting

confidence: 73%

Japanese subject subpopulation analysis of B-LONG: a Phase 3 study of long-acting recombinant factor IX Fc fusion protein

Shima

Fukutake

Hanabusa

et al. 2015

Nihon Kessen Shiketsu Gakkaishi

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“…Thirty-three genetic variations were found in FCGRT, but the two non-synonymous variations characterized were similar to the wild type in their intracellular localization and antibody recycling efficiencies. 11) The variable number of tandem repeat (VNTR) found in human FCGRT promoter influenced the transcriptional activity of FCGRT in monocytes, but has not shown association with risk for glomerular nephritis or with transfer of IgG from mother to fetus. 12) In the present study, the genetic variants found in cynomolgus and rhesus FCGRT and B2M did not appear to influence the FcRn function.…”

Section: Resultsmentioning

confidence: 99%

Polymorphisms of Neonatal Fc Receptor in Cynomolgus and Rhesus Macaques

Uno

Utoh

Iwasaki

2014

Drug Metabolism and Pharmacokinetics

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Neonatal Fc receptor (FcRn), a heterodimer of MHC class I-like protein and β2-microglobulin, encoded by FCGRT and B2M, respectively, is important for recycling immunoglobulin G (IgG) antibodies by binding with the Fc region of IgG. Cynomolgus macaques are important animal species used in the evaluation of therapeutic antibodies, largely due to sequence similarities of target proteins to those of humans. Because the function of FcRn could be modified by mutations in FCGRT or B2M, 71 cynomolgus and 24 rhesus macaques were analyzed in the present study. A total of 21 variants were identified, of which 4 were non-synonymous in FCGRT. Fifteen variants were unique to cynomolgus macaques, of which 3, 2, and 5 were unique to cynomolgus macaques bred in China (MacfaCHN), Cambodia (MacfaCAM), and Indonesia (MacfaIDN), respectively. Five variants were shared by MacfaCHN and MacfaCAM, but not by MacfaIDN. In B2M, only 5 variants were found, including 2 non-synonymous variants. Tissue expression analysis showed that cynomolgus FCGRT and B2M were widely expressed in the 10 tissue types analyzed. None of the non-synonymous variants of FCGRT or B2M found changes in the amino acid residues known to be important for FcRn function, suggesting that substantial inter-animal variability of FcRn is not expected for the cynomolgus macaques analyzed.

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“…mAbs against soluble antigens are primarily eliminated by Fc receptor‐mediated clearance, which involves a non‐specific common pathway for endogenous IgG and mAbs via FcRn and FcγR, a process that shows linear pharmacokinetics. Several reports have described ethnic differences in these pathways . For FcRn, genetic polymorphisms of FCGRT were reported to show ethnic differences, as the mean allelic frequency of the variable number of tandem repeats was 0.032 in Japanese individuals versus 0.075 in Caucasians .…”

Section: Ethnic Differences In the Pharmacokinetics Of Monoclonal Antmentioning

confidence: 99%

“…Several reports have described ethnic differences in these pathways . For FcRn, genetic polymorphisms of FCGRT were reported to show ethnic differences, as the mean allelic frequency of the variable number of tandem repeats was 0.032 in Japanese individuals versus 0.075 in Caucasians . However, the impact of these genetic variations on the function of FcRn is yet to be established.…”

Section: Ethnic Differences In the Pharmacokinetics Of Monoclonal Antmentioning

confidence: 99%

A comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in Japan: Are Japanese phase I studies still needed?

Chiba¹,

Yoshitsugu

Kyosaka³

et al. 2014

The Journal of Clinical Pharmacology

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Ethnic evaluation of the pharmacokinetics and safety of new drugs is required in Japan before implementing bridging or joining global studies. As therapeutic monoclonal antibodies (mAbs) show limited ethnic differences, their pharmacokinetics and safety in Japanese individuals could be estimated from prior non-Japanese studies. Therefore, there is potential to re-evaluate the development program for mAbs in Japan. We reviewed the pharmacokinetics of mAbs approved in Japan. Although some differences had been observed in pharmacokinetics of mAbs between Japanese and non-Japanese populations (mainly Caucasians), these differences were attributed to differences of body weight and/or antigen levels. Moreover, the influential factors can be estimated without conducting regional pharmacokinetic/safety studies. The pharmacokinetics of some mAbs is presumably non-linear and show differences between healthy volunteers and patients because of differences in antigen levels. However, for 10/24 mAbs approved in Japan, Japanese healthy volunteer studies were conducted before the patient studies. Additionally, for the mAbs that showed ethnic differences in pharmacokinetics, the doses selected in subsequent patient studies were the same as the doses approved in the United States. In this review, we discuss new drug development strategies in various regions, and assess the need for regional pharmacokinetics/safety studies before joining global studies.

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Genetic Polymorphisme of FCGRT Encoding FcRn in a Japanese Population and Their Functional Analysis

Cited by 19 publications

References 23 publications

Japanese subject subpopulation analysis of B-LONG: a Phase 3 study of long-acting recombinant factor IX Fc fusion protein

Japanese subject subpopulation analysis of B-LONG: a Phase 3 study of long-acting recombinant factor IX Fc fusion protein

Polymorphisms of Neonatal Fc Receptor in Cynomolgus and Rhesus Macaques

A comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in Japan: Are Japanese phase I studies still needed?

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