Complement activation determines the therapeutic activity of rituximab in vivo

Nicola Di Gaetano, Elena Cittera, Rachele Nota, Annunciata Vecchi, Valeria Grieco, Eugenio Scanziani, Marina Botto, Martino Introna, Josée Golay

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Abstract

Rituximab is an anti-CD20 chimeric mAb effective for the treatment of B-NHL. It can lyse lymphoma cells in vitro through both C- and Ab-dependent cellular cytotoxicity. The mechanism of action of rituximab in vivo is however still unclear. We have set up a new in vivo model in nonimmunodeficient mice by stable transduction of the human CD20 cDNA in the murine lymphoma line EL4. Animals injected i.v. with the EL4-CD20+ lymphoma cells died within 30 days with evident liver, spleen, and bone marrow involvement, confirmed by immunohistochemistry and PCR analysis. A single injection of rituximab or the murine anti-CD20 Ab 1F5, given i.p. 1 day after the tumor, cured 100% of the animals. Indeed, at week 4 after tumor cell inoculation, CD20+ cells were undetectable in all organs analyzed in rituximab-treated animals, as determined by immunohistochemistry and PCR. Rituximab had no direct effect on tumor growth in vitro. Depletion of either NK cells or neutrophils or both in tumor-injected animals did not affect the therapeutic activity of the drug. Similarly, rituximab was able to eradicate tumor cells in athymic nude mice, suggesting that its activity is T cell independent. In contrast, the protective activity of rituximab or the 1F5 Ab was completely abolished in syngeneic knockout animals lacking C1q, the first component of the classical pathway of C (C1qa-/-). These data demonstrate that C activation is fundamental for rituximab therapeutic activity in vivo.

Original languageEnglish
Pages (from-to)1581-1587
Number of pages7
JournalJournal of Immunology
Volume171
Issue number3
Publication statusPublished - Aug 1 2003

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Complement Activation
Lymphoma
Therapeutics
Neoplasms
Nude Mice
Immunohistochemistry
Polymerase Chain Reaction
Rituximab
Natural Killer Cells
Neutrophils
Spleen
Complementary DNA
Bone Marrow
T-Lymphocytes
Injections
Liver
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology

Cite this

Di Gaetano, N., Cittera, E., Nota, R., Vecchi, A., Grieco, V., Scanziani, E., ... Golay, J. (2003). Complement activation determines the therapeutic activity of rituximab in vivo. Journal of Immunology, 171(3), 1581-1587.

Complement activation determines the therapeutic activity of rituximab in vivo. / Di Gaetano, Nicola; Cittera, Elena; Nota, Rachele; Vecchi, Annunciata; Grieco, Valeria; Scanziani, Eugenio; Botto, Marina; Introna, Martino; Golay, Josée.

In: Journal of Immunology, Vol. 171, No. 3, 01.08.2003, p. 1581-1587.

Research output: Contribution to journalArticle

Di Gaetano, N, Cittera, E, Nota, R, Vecchi, A, Grieco, V, Scanziani, E, Botto, M, Introna, M & Golay, J 2003, 'Complement activation determines the therapeutic activity of rituximab in vivo', Journal of Immunology, vol. 171, no. 3, pp. 1581-1587.
Di Gaetano N, Cittera E, Nota R, Vecchi A, Grieco V, Scanziani E et al. Complement activation determines the therapeutic activity of rituximab in vivo. Journal of Immunology. 2003 Aug 1;171(3):1581-1587.
Di Gaetano, Nicola ; Cittera, Elena ; Nota, Rachele ; Vecchi, Annunciata ; Grieco, Valeria ; Scanziani, Eugenio ; Botto, Marina ; Introna, Martino ; Golay, Josée. / Complement activation determines the therapeutic activity of rituximab in vivo. In: Journal of Immunology. 2003 ; Vol. 171, No. 3. pp. 1581-1587.
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