In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas

Manches, Olivier; Lui, Gabrielle; Chaperot, Laurence; Gressin, Rémy; Molens, Jean-Paul; Jacob, Marie Christine; Sotto, J. J.; Leroux, Dominique; Bensa, Jean Claude; Plumas, Joël

doi:10.1182/blood-2002-02-0469

Cited by 326 publications

(263 citation statements)

References 32 publications

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Section: Introductionmentioning

confidence: 97%

“…Analysis of primary non-Hodgkin's lymphoma cells for their susceptibility to Rituximab-mediated killing showed that Rituximab had a negligible apoptotic effect [15]. 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%

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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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Section: Introductionmentioning

confidence: 97%

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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“…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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“…Different factors may contribute to this therapeutic failure of CD20-targeted therapies, including CD20 downregulation (Foran et al, 2001), altered signal transduction pathways (Pommier et al, 2004), circulating CD20 protein (Manshouri et al, 2003), polymorphisms in the FcgRIII receptor (Cartron et al, 2002) and an increase in complement-resistant proteins like CD55 or CD59 (Treon et al, 2001;Manches et al, 2003). The immunohistochemical analysis of the presented case series of relapsing CBCL lesions revealed an unchanged CD20 expression.…”

Section: Discussionmentioning

confidence: 73%

Bcl-2 expression in rituximab refractory cutaneous B-cell lymphoma

et al. 2007

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Rituximab has been established as an effective and safe therapy for cutaneous B-cell lymphoma (CBCL). Different survival pathways, that is the Raf/MEK/Erk-or the p38MAPK cascade, have been suggested as downstream mediators of rituximab and may be involved in treatment failure. Biopsies from four patients, suffering from different subtypes of CBCL, which were obtained at various time points of relapse during or after therapy with 375 mg rituximab per m 2 of body surface area, were analysed for the expression of CD20, CD3, Ki-67, Raf-kinase inhibitory protein (RKIP) and bcl-2 by immunohistochemistry. No CD20-loss variants, that is the suggested main tumour escape mechanism to rituximab therapy, were observed in any specimen of relapsing CBCL. Notably, the expression of proapoptotic RKIP remained increased in these tumour samples. This was concomitated by a constant to slightly reduced proliferation status as demonstrated by Ki-67 staining. However, relapsing CBCL exhibited a strong upregulation of the antiapoptotic molecule bcl-2 in comparison to pretherapeutic levels. The immunohistochemical analyses of this case series of rituximab refractory CBCL suggest that upregulation of bcl-2 may play a major role in therapy resistance. The exact in vivo mechanisms of rituximab still remain elusive but likely include antibody-dependent cellular cytotoxicity (ADCC), complement-mediated lysis (CDC) and immune responses (Reff et al, 1994;Selenko et al, 2001). Furthermore, rituximab inhibits crucial survival pathways by upregulating the Raf-kinase inhibitory protein (RKIP), thus directly modifying the extracellular signal-regulated kinase1/2-and nuclear factor-k B, respectively (Jazirehi and Bonavida, 2005).Despite a high initial response rate, local or distant recurrence of CBCL is frequently observed in rituximab therapy. To delineate possible factors predicting or being associated with relapse, we scrutinised recurrent CBCL from four patients before, during and after systemic rituximab therapy. PATIENTS AND METHODS Patient characteristicsFour patients with multifocal CBCL (classified according to the WHO-EORTC classification for primary cutaneous lymphoma (Willemze et al, 2005)) were treated with rituximab intravenously at doses of 375 mg m À2 body surface area at

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In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas

Cited by 326 publications

References 32 publications

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

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

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

Bcl-2 expression in rituximab refractory cutaneous B-cell lymphoma

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