The autophilic anti-CD20 antibody DXL625 displays enhanced potency due to lipid raft-dependent induction of apoptosis

Marc G. Bingaman, Gargi D. Basu, Tiana C. Golding, Samuel K. Chong, Andrew J. Lassen, Thomas J. Kindt, Christopher A. Lipinski

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Despite widespread use of anti-CD20 antibodies as therapeutic agents for oncologic and autoimmune indications, precise descriptions of killing mechanisms remain incomplete. Complement-dependent cytolysis and antibody-dependent cell-mediated cytotoxicity are indicated as modes of target cell depletion; however, the importance of apoptosis induction is controversial. Studies showing that the therapeutic anti-CD20 antibody rituximab (Rituxan) mediates apoptosis of tumor cell targets in vitro after cross-linking by anti-Fc reagents suggest that enhancement strategies applied to Fc-independent activities for anti-CD20 antibodies could improve therapeutic efficacy. An anti-CD20 antibody designated DXL625, with autophilic properties such as increased binding avidity, is shown here to independently induce caspase-mediated apoptosis of an established B-cell lymphoma line in vitro. Depletion of membrane cholesterol or chelation of extracellular calcium abrogated the pro-apoptotic activity of DXL625, indicating that intact lipid rafts and calcium are required for this activity. The Fc-mediated complement-dependent and antibody-dependent cellular killing mechanisms are maintained by DXL625 despite conjugation of the parental Rituxan antibody to the autophilic DXL peptide sequence. This study shows a strategy for improving anti-CD20 immunotherapy by endowing therapeutic antibodies with self-interacting properties.

Original languageEnglish (US)
Pages (from-to)532-542
Number of pages11
JournalAnti-cancer drugs
Volume21
Issue number5
DOIs
StatePublished - Jun 1 2010

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Keywords

  • Apoptosis
  • CD20 receptor
  • DXL625
  • Rituxan

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

Cite this

Bingaman, M. G., Basu, G. D., Golding, T. C., Chong, S. K., Lassen, A. J., Kindt, T. J., & Lipinski, C. A. (2010). The autophilic anti-CD20 antibody DXL625 displays enhanced potency due to lipid raft-dependent induction of apoptosis. Anti-cancer drugs, 21(5), 532-542. https://doi.org/10.1097/CAD.0b013e328337d485