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A nonfucosylated human antibody to CD19 with potent B-cell depletive activity for therapy of B-cell malignancies

  • Pina M. CardarelliEmail author
  • Chetana Rao-Naik
  • Sharline Chen
  • Haichun Huang
  • Amie Pham
  • Maria-Cristina Moldovan-Loomis
  • Chin Pan
  • Ben Preston
  • David Passmore
  • Jie Liu
  • Michelle R. Kuhne
  • Alison Witte
  • Diann Blanset
  • David J. King
Original Article

Abstract

A human anti-CD19 antibody was expressed in fucosyltransferase-deficient CHO cells to generate nonfucosylated MDX-1342. Binding of MDX-1342 to human CD19-expressing cells was similar to its fucosylated parental antibody. However, MDX-1342 exhibited increased affinity for FcγRIIIa-Phe158 and FcγRIIIa-Val158 receptors as well as enhanced effector cell function, as demonstrated by increased potency and efficacy in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis assays. MDX-1342 showed dose-dependent improvement in survival using a murine B-cell lymphoma model in which Ramos cells were administered systemically. In addition, low nanomolar binding to cynomolgus monkey CD19 and increased affinity for cynomolgus monkey FcγRIIIa was observed. In vivo administration of MDX-1342 in cynomolgus monkeys revealed potent B-cell depletion, suggesting its potential utility as a B-lymphocyte depletive therapy for malignancies and autoimmune indications.

Keywords

CD19 B-cell lymphoma ADCC FcγRIIIa Therapeutic antibodies 

Notes

Acknowledgments

We thank Dr. Michael Yellin and Dr. Albert Assad for productive discussions. We also thank Catherine Bolger for her excellent suggestions and assistance in editing this manuscript.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Pina M. Cardarelli
    • 1
    Email author
  • Chetana Rao-Naik
    • 2
  • Sharline Chen
    • 1
  • Haichun Huang
    • 3
  • Amie Pham
    • 3
  • Maria-Cristina Moldovan-Loomis
    • 1
  • Chin Pan
    • 1
  • Ben Preston
    • 1
  • David Passmore
    • 4
  • Jie Liu
    • 5
  • Michelle R. Kuhne
    • 1
  • Alison Witte
    • 1
  • Diann Blanset
    • 6
  • David J. King
    • 7
  1. 1.Department of Cell Biology and PharmacologyMedarexSunnyvaleUSA
  2. 2.Department of Protein ChemistryMedarexSunnyvaleUSA
  3. 3.Department of Hybridoma ResearchMedarexMilpitasUSA
  4. 4.Department of Bioanalytical ChemistryMedarexSunnyvaleUSA
  5. 5.Department of Discovery ResearchMedarexMilpitasUSA
  6. 6.Department of Preclinical DevelopmentMedarexBloomsburyUSA
  7. 7.AnaptysBioSan DiegoUSA

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