論文 - 増井　翔

Low serum concentrations of bevacizumab and nivolumab owing to excessive urinary loss in patients with proteinuria: a case series.

Masuda T, Funakoshi T, Horimatsu T, Yamamoto S, Matsubara T, Masui S, Nakagawa S, Ikemi Y, Yanagita M, Muto M, Terada T, Yonezawa A

Cancer chemotherapy and pharmacology 94 （ 4 ） 615 - 622 2024年03月

ISSN  0344-5704

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Comparison of safety and effectiveness between etanercept biosimilar LBEC0101 and reference in patients with rheumatoid arthritis in real-world data using the KURAMA cohort.

Kawakami T, Masui S, Onishi A, Onizawa H, Fujii T, Murakami K, Murata K, Tanaka M, Shimada T, Nakagawa S, Matsuda S, Morinobu A, Terada T, Yonezawa A

Modern rheumatology 34 （ 6 ） 1135 - 1141 2024年03月

ISSN  1439-7595

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Clinical characteristics of cryopyrin-associated periodic syndrome and long-term real-world efficacy and tolerability of canakinumab in Japan: results of a nationwide survey

Takayuki Miyamoto, Kazushi Izawa, Sho Masui, Atsue Yamazaki, Yuichi Yamasaki, Tadashi Matsubayashi, Mayuka Shiraki, Hidenori Ohnishi, Junko Yasumura, Kawabe Tomohiro, Takako Miyamae, Tomoyo Matsubara, Naoya Arakawa, Takashi Ishige, Takumi Takizawa, Asami Shimbo, Masaki Shimizu, Naoki Kimura, Yuichi Maeda, Yuta Maruyama, Tomonari Shigemura, Junichi Furuta, Satoshi Sato, Hiroshi Tanaka, Miharu Izumikawa, Masahiro Yamamura, Toshio Hasegawa, Hiroshi Kaneko, Yasuo Nakagishi, Naoko Nakano, Yasunori Iida, Tamaki Nakamura, Hiroyuki Wakiguchi, Takayuki Hoshina, Toshinao Kawai, Kosaku Murakami, Shuji Akizuki, Akio Morinobu, Koichiro Ohmura, Katsuhide Eguchi, Motoshi Sonoda, Masataka Ishimura, Kenji Furuno, Momoko Kashiwado, Masaaki Mori, Kimito Kawahata, Koremasa Hayama, Kumiko Shimoyama, Natsuko Sasaki, Taisuke Ito, Hiroaki Umebayashi, Tae Omori, Seiko Nakamichi, Tomotsune Dohmoto, Yasuyuki Hasegawa, Hisashi Kawashima, Shojiro Watanabe, Yuichiro Taguchi, Haruna Nakaseko, Naomi Iwata, Hiroki Kohno, Taiki Ando, Yasuhiko Ito, Yuko Kataoka, Takako Saeki, Utako Kaneko, Ayako Murase, Seira Hattori, Tomo Nozawa, Kenichi Nishimura, Reiji Nakano, Misa Watanabe, Masato Yashiro, Tomonori Nakamura, Toshihiko Komai, Kentaro Kato, Yoshitaka Honda, Eitaro Hiejima, Atsushi Yonezawa, Kazuhisa Bessho, Satoshi Okada, Osamu Ohara, Junko Takita, Takahiro Yasumi, Ryuta Nishikomori; Japan CAPS working group

Arthritis Rheumatol 2024年01月

研究論文（学術雑誌）, 共著, 査読有り

Serum Concentrations of Infliximab and IL-6 for Predicting One-Year Discontinuation of Infliximab Treatment Owing to Secondary Non-response in Patients with Rheumatoid Arthritis.

Masui S, Yonezawa A, Nakamura M, Onishi A, Hashimoto M, Onizawa H, Fujii T, Murakami K, Murata K, Tanaka M, Yokoyama K, Iwamoto N, Shimada T, Itohara K, Hira D, Nakagawa S, Imai S, Nakagawa T, Hayakari M, Matsuda S, Morinobu A, Terada T, Matsubara K

Biological & pharmaceutical bulletin （Biological and Pharmaceutical Bulletin）  46 （ 8 ） 1112 - 1119 2023年

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  ISSN  0918-6158

　概要を見る

Secondary non-response to infliximab (IFX) occurs in some patients with rheumatoid arthritis (RA). Although therapeutic drug monitoring (TDM) is a useful tool to optimize IFX therapy, it is unclear whether it can help to identify the risk of secondary non-response. This study aimed to explore the utility of serum levels of IFX or other biomarkers to predict IFX discontinuation owing to secondary non-response. A single-center, retrospective study was conducted using the Kyoto University Rheumatoid Arthritis Management Alliance cohort database between 2011 and 2020. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. An electrochemiluminescence assay was used to quantify serum levels of tumor necrosis factor-α and interleukin-6 and detect anti-drug antibodies. Eighty-four out of 310 patients were eligible for this study. The cutoff levels of biomarkers were determined by receiver operating characteristic analysis. IFX persistence was similar between groups stratified using IFX levels, tumor necrosis factor-α levels, interleukin-6 levels, and anti-drug antibodies positivity. The group with lower IFX and higher interleukin-6 levels had the worst therapy persistence (p=0.017) and the most frequent disease worsening (90.0%, p<0.001). Evaluating both interleukin-6 and IFX levels, not just IFX alone, enabled us to identify patients at risk of discontinuing IFX treatment. These findings support the utility of measuring IFX and interleukin-6 levels for successful maintenance therapy for RA.

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N-terminus of Etanercept is Proteolytically Processed by Dipeptidyl Peptidase-4.

Masui S, Yonezawa A, Yokoyama K, Iwamoto N, Shimada T, Onishi A, Onizawa H, Fujii T, Murakami K, Murata K, Tanaka M, Nakagawa S, Hira D, Itohara K, Imai S, Nakagawa T, Hayakari M, Matsuda S, Morinobu A, Terada T, Matsubara K

Pharmaceutical research （Pharmaceutical Research）  39 （ 10 ） 2541 - 2554 2022年10月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  ISSN  0724-8741

　概要を見る

Purpose: Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor (TNF) receptor and the Fc portion of human immunoglobulin G1. The N-terminus of ETN has a putative sequence cleaved by dipeptidyl peptidase-4 (DPP-4). The purpose of this study was to investigate the biotransformation of ETN in humans and mice and evaluate its effects on functional properties. Methods: An analytical method using liquid chromatography-mass spectrometry (LC–MS/MS) was established. The N-terminal heterogeneity of ETN was assessed in the serum of patients with rheumatoid arthritis or mice receiving ETN. The in vitro N-terminal truncation was explored using recombinant DPP-4. The binding affinity to TNF-α or TNF-β was investigated using an in-house enzyme-linked immunosorbent assay. Results: In the formulations, about 90% of ETN had an intact N-terminus, while the N-terminal truncated form was most abundant in the serum of the patients with rheumatoid arthritis and mice. Recombinant human DPP-4 cleaved two amino acids from the N-terminus of ETN in vitro. Sitagliptin, a DPP-4 inhibitor, inhibited N-terminal truncation both in vivo and in vitro. However, N-terminal truncation did not affect the binding ability to TNF-α or TNF-β and the pharmacokinetics of ETN. ETN biosimilars exhibited similar characteristics to the reference product in vivo and in vitro. Conclusions: ETN undergoes N-terminal truncation in the body, and DPP-4 cleaves exogenous ETN via N-terminal proteolysis. The application of an MS-based assay will detect novel biotransformation of therapeutic proteins.

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Infliximab Treatment Persistence among Japanese Patients with Chronic Inflammatory Diseases: A Retrospective Japanese Claims Data Study.

Masui S, Yonezawa A, Momo K, Nakagawa S, Itohara K, Imai S, Nakagawa T, Matsubara K

Biological & pharmaceutical bulletin （Biological and Pharmaceutical Bulletin）  45 （ 3 ） 323 - 332 2022年

研究論文（学術雑誌）, 筆頭著者, 査読有り,  ISSN  0918-6158

　概要を見る

Infliximab (IFX) has contributed to the treatment of several chronic inflammatory diseases, including Crohn's disease (CD), ulcerative colitis (UC), psoriasis (Pso), and rheumatoid arthritis (RA). However, the loss of response in some patients with long-term IFX therapy has been a major problem. Randomized controlled trials (RCTs) are limited in their short duration and lack of generalizability to the real-world population. We aimed to describe the persistence rates of IFX therapy to estimate its long-term effectiveness in clinical practice. Claims data from the Japan Medical Data Center database from January 2005 to June 2017 were used. The study population was identified based on the International Classification of Diseases, 10th Revision and the Anatomical Therapeutic Chemical Classification System. The 5-year persistence rates of IFX therapy were estimated using the Kaplan-Meier method. Overall, 281, 235, 41, and 222 patients with CD, UC, Pso, and RA, respectively, were selected. The 5-year persistence rates for IFX claims were 62.9, 38.9, 22.1, and 28.1% in patients with CD, UC, Pso, and RA, respectively. Patients with CD and UC administered IFX beyond the median dose had higher persistence rates. In patients with RA, female sex and no prior use of other biologics were associated with longer persistence. In conclusion, IFX persistence rates differed across chronic inflammatory diseases, which did not correspond to the results of the major RCTs. Factors associated with longer IFX persistence were identified in each disease group. Our findings may provide useful information to facilitate the proper use of IFX.

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Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data.

Nakae K, Masui S, Yonezawa A, Hashimoto M, Watanabe R, Murata K, Murakami K, Tanaka M, Ito H, Yokoyama K, Iwamoto N, Shimada T, Nakamura M, Denda M, Itohara K, Nakagawa S, Ikemi Y, Imai S, Nakagawa T, Hayakari M, Matsubara K

PloS one （PLoS ONE）  16 （ 10 ） e0258601 2021年

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り

　概要を見る

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use.

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Plasma infliximab monitoring contributes to optimize Takayasu arteritis treatment: a case report

Sho Masui, Atsushi Yonezawa, Kazushi Izawa, Makoto Hayakari, Kayoko Asakura, Risa Taniguchi, Masahiko Isa, Hirofumi Shibata, Takahiro Yasumi, Ryuta Nishikomori, Junko Takita, Kazuo Matsubara

Journal of Pharmaceutical Health Care and Sciences （BMC）  5 （ 9 ）  2019年05月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り

Concentration and Glycoform of Rituximab in Plasma of Patients with B Cell Non-Hodgkin's Lymphoma.

Yonezawa A, Otani Y, Kitano T, Mori M, Masui S, Isomoto Y, Tsuda M, Imai S, Ikemi Y, Denda M, Sato Y, Nakagawa S, Omura T, Nakagawa T, Yano I, Hayakari M, Takaori-Kondo A, Matsubara K

Pharmaceutical research （Pharmaceutical Research）  36 （ 6 ） 82 2019年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0724-8741

　概要を見る

Purpose: Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. Methods: Twenty B cell non-Hodgkin’s lymphoma patients who were treated with rituximab for the first time or after more than one year’s abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. Results: Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. Conclusion: Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.

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Analysis of Glycoforms and Amino Acids in Infliximab and a Biosimilar Product Using New Method with LC/TOF-MS.

Tsuda M, Otani Y, Yonezawa A, Masui S, Ikemi Y, Denda M, Sato Y, Nakagawa S, Omura T, Imai S, Nakagawa T, Hayakari M, Matsubara K

Biological & pharmaceutical bulletin （Biological and Pharmaceutical Bulletin）  41 （ 11 ） 1716 - 1721 2018年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0918-6158

　概要を見る

Biosimilar products of therapeutic antibodies have been launched all over the world. They can relieve some of the economic burden of medicines. Although clinical trials have demonstrated the equivalency of biosimilar products with their reference product, biosimilar products are not commonly used in clinical practice. One reason is that the structural difference between the reference product and a biosimilar one remains unclear. We analyzed glycoforms and amino acids of an infliximab biosimilar product approved in Japan compared to that of the reference product (Remicade®). By combination of papain digestion and LC/ time-of-flight (TOF)-MS, we established a valuable method to analyze these therapeutic antibodies. Nine glycoforms were detected in infliximab, and a difference in amino acids was observed. In the glycoforms of MMF, MGnF/GnMF, GnGn, GnGnF, AGnF/GnAF, and AAF, the relative intensities were significantly different between the reference and biosimilar product. Furthermore, we elucidated that the content rate of the C-terminal lysine was different among glycoforms. In conclusion, our analytical method can analyze not only amino acids but also carbohydrate chains of therapeutic antibodies, and will provide a useful strategy to evaluate bio-medicines including biosimilar antibodies.

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