Complement Activation Determines the Therapeutic Activity of Rituximab In Vivo

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

doi:10.4049/jimmunol.171.3.1581

Cited by 499 publications

(346 citation statements)

References 48 publications

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“…In animal models, the activity of rituximab was completely abolished when administered to C1q-deficient knockout mice, demonstrating that complement activation is fundamental for rituximab efficacy (42). In the present study, no relation to the initial complement levels and renal response could be demonstrated (data not shown).…”

Section: Discussioncontrasting

confidence: 59%

Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide‐resistant proliferative lupus nephritis

Gunnarsson¹,

Sundelin²,

Jónsdóttir³

et al. 2007

Arthritis & Rheumatism

221

149

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Objective. Rituximab is a monoclonal antibody directed against the CD20 marker of B cells. Because of its ability to deplete B lymphocytes, it has been suggested that the drug could be of benefit in B celldependent diseases, including systemic lupus erythematosus (SLE). The purpose of this study was to investigate the histopathologic and clinical effects of combination treatment with rituximab and cyclophosphamide (CYC) in patients with CYC-resistant proliferative lupus nephritis.Methods. Seven female patients with proliferative lupus nephritis were treated with rituximab in combination with CYC. Renal biopsies were performed before treatment and during followup. SLE activity was evaluated by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group index. In 6 of the 7 patients, immunostaining of lymphocyte subpopulations in the renal tissue was performed before treatment and during followup.Results. At 6 months of followup, significant clinical improvement was noted, with a reduction in SLEDAI scores (from a mean of 15 to 3), anti-doublestranded DNA antibody levels (from a mean of 174 IU/ml to 56 IU/ml), and anti-C1q antibody levels (from a mean of 35 units/ml to 22 units/ml). On repeat renal biopsy, improvement in the histopathologic class of nephritis occurred in a majority of patients, and a decrease in the renal activity index was noted (from 6 to 3). A reduction in the number of CD3, CD4, and CD20 cells in the renal interstitium was noted in 50% of the patients on repeat biopsy. Conclusion. At 6 months of followup, all patients had responded both clinically and histopathologically to combination therapy. For patients with proliferative lupus nephritis who fail to respond to conventional immunosuppressive therapy including CYC, combined treatment with rituximab and CYC may constitute a new treatment option.

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Section: Discussioncontrasting

confidence: 59%

Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide‐resistant proliferative lupus nephritis

Gunnarsson¹,

Sundelin²,

Jónsdóttir³

et al. 2007

Arthritis & Rheumatism

221

149

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“…CDC is clearly involved in the action of rituximab both in vitro and in preclinical mouse models (21,22,(32)(33)(34). Manches et al have also reported a correlation between in vitro sensitivity to CDC of various lymphoma subtypes and the likelihood of response to rituximab in the clinic (17).…”

Section: Discussionmentioning

confidence: 99%

“…Various in vitro and in vivo experiments have shown that elimination of CD20þ lymphoma cells by rituximab involves complement-dependent cytotoxicity (CDC; refs [16][17][18][19][20][21][22][23], direct induction of apoptotic signalling (24)(25)(26), as well as the recruitment of effector cells leading to antibody-dependent cell-mediated cytotoxicity (27). Nevertheless, the in vivo mechanism of action of and resistance to rituximab are not fully understood (28).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Studies on the Mechanism of Action and the Anti-Lymphoma Activity of the Novel Anti-CD20 Antibody GA101

Dalle

Reslan

Horts

et al. 2011

Molecular Cancer Therapeutics

114

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GA101 is a novel glycoengineered Type II CD20 monoclonal antibody. When compared with rituximab, it mediates less complement-dependent cytotoxicity (CDC). As expected for a Type II antibody, GA101 appears not to act through CDC and is more potent than the Type I antibody rituximab in inducing cell death via nonclassical induction of apoptosis cytotoxicity, with more direct cytotoxicity and more antibody-dependent cell-mediated cytotoxicity. We evaluated the antitumor activity of GA101 against the human-transformed follicular lymphoma RL model in vivo in severe combined immunodeficient mice (SCID) mice. GA101 induced stronger inhibition of tumor growth than rituximab. Combination of GA101 with cyclophosphamide in vivo confirmed the superiority of GA101 over rituximab. Neutralizing the complement system with cobra venom factor partially impaired the antitumor activity of rituximab, but had no impact on the efficacy of GA101. In vitro GA101 more potently induced cell death of RL cells than rituximab. The expression of a limited number of genes was found to be induced by both antibodies after exposure in vitro. Among these, early growth response 1 and activation transcription factor 3 were confirmed to be increased at the protein level, suggesting a possible role of these proteins in the apoptotic signalling of anti-CD20 antibodies. These data imply that GA101 is superior to rituximab not only as a single agent, but also in combination with chemotherapy. These data suggest the presence of novel signalization pathways activated after exposure to anti-CD20 antibodies.

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“…Furthermore, the susceptibility of all the cells examined for ADCC did not correlate with the clinical response to the Ab, whereas the in vitro cell-sensitivity to CDC was found to be the best predictor of the in vivo effect of Rituximab [15]. The important role of CDC in mediating the therapeutic effect of Rituximab was supported by the finding that the growth of a murine lymphoma transfected with CD20 was inhibited by Rituximab in complement-sufficient but not in C1q-deficient mice [16].…”

Section: Introductionmentioning

confidence: 99%

Controlling complement resistance in cancer by using human monoclonal antibodies that neutralize complement-regulatory proteins CD55 and CD59

et al. 2005

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Expression of the complement-regulatory proteins (CRP) CD46, CD55 and CD59 represents a strategy used by tumor cells to evade complement-dependent cell cytoxicity stimulated by monoclonal antibodies. We have isolated two single-chain variable fragments (scFv) to CD55 and CD59 from a human phage-display library and from these scFv we have produced two miniantibodies (MB), MB-55 (against CD55) and MB-59 (against CD59), containing the human hinge-CH2-CH3 domains of IgG1. The specificity of the two MB for the corresponding CRP was assessed by ELISA using purified CD46, CD55 and CD59. MB-55 and MB-59 neutralized the inhibitory activity of CD55 and CD59, respectively, restoring the complement-mediated lysis of sheep and guinea pig erythrocytes that was otherwise inhibited by the two CRP. FACS analysis revealed binding of MB-55 and MB-59 to the lymphoma cell line Karpas 422. The two MB induced a two-fold increase in the complement-dependent killing of these cells stimulated by Rituximab, a chimeric anti-CD20 monoclonal antibody. Transfection of HEK293T cells with vectors encoding MB-55 or MB-59 markedly reduced the expression of CD55 and CD59. We conclude that the human antibodies MB-55 and MB-59 may represent a therapeutic tool to increase the complement-dependent killing activity of Rituximab in the treatment of non-Hodgkin's lymphoma.

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Complement Activation Determines the Therapeutic Activity of Rituximab In Vivo

Cited by 499 publications

References 48 publications

Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide‐resistant proliferative lupus nephritis

Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide‐resistant proliferative lupus nephritis

Preclinical Studies on the Mechanism of Action and the Anti-Lymphoma Activity of the Novel Anti-CD20 Antibody GA101

Controlling complement resistance in cancer by using human monoclonal antibodies that neutralize complement-regulatory proteins CD55 and CD59

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