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

  • Atushi YonezawaEmail author
  • Yuki Otani
  • Toshiyuki Kitano
  • Mayuko Mori
  • Sho Masui
  • Yui Isomoto
  • Masahiro Tsuda
  • Satoshi Imai
  • Yasuaki Ikemi
  • Masaya Denda
  • Yuki Sato
  • Shunsaku Nakagawa
  • Tomohiro Omura
  • Takayuki Nakagawa
  • Ikuko Yano
  • Makoto Hayakari
  • Akifumi Takaori-Kondo
  • Kazuo Matsubara
Research Paper
  • 53 Downloads

Abstract

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.

Key Words

carbohydrate chain LC/TOF-MS pharmacokinetics rituximab therapeutic monoclonal antibody 

Abbreviations

ADCC

Antibody-dependent cellular cytotoxicity

B-NHL

B cell non-Hodgkin’s lymphoma

CHOP

Cyclophosphamide, doxorubicin, vincristine and prednisone

DLBCL

Diffuse large B cell lymphoma

ELISA

Enzyme-linked immunosorbent assay

Fab

Fragment antigen-binding

Fc

Fragment crystallizable

FL

Follicular lymphoma

LC/TOF-MS

Liquid chromatograph time-of-flight mass spectrometer

mAb

Monoclonal antibody

NK cell

Natural killer cell

nSMOL

Nano-Surface and Molecular-Orientation Limited

PBMC

Peripheral blood mononuclear cell

R-CHOP

CHOP chemotherapy in combination with rituximab

R-CVP

Cyclophosphamide, vincristine and prednisone chemotherapy in combination with rituximab

sIL-2R

Soluble Interleukin-2 receptor.

Notes

Acknowledgments and Disclosures

This work was supported by the Research on Regulatory Harmonization and Evaluation of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics from the Japan Agency for Medical Research and development, AMED, the Japan Research Foundation for Clinical Pharmacology, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research to A.Y. The authors are grateful to all the medical staff of Department of Hematology, Kyoto University Hospital. All authors have no conflicts of interest to declare. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the Ethics Committee of Kyoto University Graduate School and Faculty of Medicine and Kyoto University Hospital (E2472), and was registered at the University Hospital Medical Information Network-Clinical Trial Registry System (UMIN000016713). Written informed consent was obtained from all individual participants included in the study.

Supplementary material

11095_2019_2624_MOESM1_ESM.xlsx (31 kb)
ESM 1 (XLSX 31 kb)
11095_2019_2624_MOESM2_ESM.docx (7.5 mb)
ESM 2 (DOCX 7666 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Atushi Yonezawa
    • 1
    • 2
    Email author
  • Yuki Otani
    • 1
  • Toshiyuki Kitano
    • 3
    • 4
  • Mayuko Mori
    • 1
    • 2
  • Sho Masui
    • 1
    • 2
  • Yui Isomoto
    • 1
  • Masahiro Tsuda
    • 1
    • 2
  • Satoshi Imai
    • 1
  • Yasuaki Ikemi
    • 1
  • Masaya Denda
    • 1
    • 2
  • Yuki Sato
    • 1
  • Shunsaku Nakagawa
    • 1
  • Tomohiro Omura
    • 1
  • Takayuki Nakagawa
    • 1
  • Ikuko Yano
    • 1
    • 2
    • 5
  • Makoto Hayakari
    • 1
  • Akifumi Takaori-Kondo
    • 3
  • Kazuo Matsubara
    • 1
  1. 1.Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan
  2. 2.Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
  3. 3.Department of Hematology and Oncology, Graduate School of MedicineKyoto UniversityKyotoJapan
  4. 4.Department of HematologyKitano HospitalOsakaJapan
  5. 5.Department of PharmacyKobe University HospitalKobeJapan

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