Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies

Okrój, Marcin; Österborg, Anders; Blom, Anna M.

doi:10.1016/j.ctrv.2012.10.008

Cited by 66 publications

(46 citation statements)

References 93 publications

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“…Using sandwich ELISAs, we analysed plasma collected from 31 patients with various B cell malignancies treated with the CD20 mAbs rituximab or ofatumumab. Upon binding to target cell, anti-CD20 mAbs are expected to activate the classical complement pathway but it is not clear, which effector arm of the complement system contribute to the therapeutic effect (Okroj et al, 2013b). Also, it is not always the case that complement attack on tumor cells will proceed to the lytic stage, as malignant B cells may shed CD20-mAb complexes (Taylor and Lindorfer, 2014) and widely express the complement inhibitors CD46 and CD55 preventing C5 cleavage (Okroj et al, 2013a).…”

Section: Measurement Of Soluble Markers Of Complement Activation In Pmentioning

confidence: 99%

Antibodies reactive to cleaved sites in complement proteins enable highly specific measurement of soluble markers of complement activation

Blom

Österborg

Mollnes

et al. 2015

Molecular Immunology

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Antibodies reactive to cleaved sites in complement proteins enable highly specific measurement of soluble markers of complement activation.Blom, Anna; Österborg, Anders; Mollnes, Tom E; Okroj, Marcin Link to publication Citation for published version (APA): Blom, A., Österborg, A., Mollnes, T. E., & Okroj, M. (2015). Antibodies reactive to cleaved sites in complement proteins enable highly specific measurement of soluble markers of complement activation. Molecular Immunology, 66(2), 164-170. DOI: 10.1016164-170. DOI: 10. /j.molimm.2015 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal AbstractAn emerging number of diseases and therapeutic approaches with defined involvement of the complement system justify a need for specific markers reflecting activation of particular effector arms of the complement cascade. Measurement of such soluble markers in circulation is a challenge since the specificity of antibodies must be limited to activated complement fragments but not predominant and ubiquitous parental molecules. Existing assays for the measurement of soluble, activated complement proteins are based on the detection of conformational neoepitopes. We tested an alternative approach based on detection of short linear neoepitopes exposed at the cleavage sites after activation of the actual complement component. Obtained antibodies reactive to C4d and C5b fragments enabled us to set up highly specific sandwich ELISAs, which ensured trustful measurements without false positive readouts characteristic for some of the widely used assays.

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Section: Measurement Of Soluble Markers Of Complement Activation In Pmentioning

confidence: 99%

Antibodies reactive to cleaved sites in complement proteins enable highly specific measurement of soluble markers of complement activation

Blom

Österborg

Mollnes

et al. 2015

Molecular Immunology

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“…Such protection may be overrun by tumor-targeted monoclonal antibodies (mAbs), which enhance the efficacy of complement-dependent cytotoxicity (CDC, attributable to lysis of target cells due to membrane attack complex formation) and lead to establishment of successful therapies. Therapeutic mAbs may exert at least two more modes of target cell killing: antibody-dependent cellular cytotoxicity (ADCC) or direct effects such as apoptotic cell death upon antibody binding [5]. Moreover, phagocytes engulf cells opsonized by antibodies and/or complement more readily.…”

Section: Introductionmentioning

confidence: 99%

Killing of CLL and NHL cells by rituximab and ofatumumab under limited availability of complement

et al. 2013

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“…IPH4102 was effective in autologous killing assays in which it induces NK cell-based lysis of autologous S ezary cells, demonstrating both the functional integrity of patients' NK cells, and the sensitivity of primary tumors to ADCC through KIR3DL2 targeting. ADCC is known to contribute to the clinical efficacy of many approved therapeutic mAbs, including anti-HER2 trastuzumab (46), anti-CD20 rituximab and obinutuzumab (44,(47)(48)(49)(50), anti-CCR4 mogamulizumab (45), or anti-EGFR cetuximab (51). Moreover, IPH4102 was found to reproducibly promote S ezary tumor cells lysis when directly incubated with patients' unsorted PBMC, hence at much less favorable effector to target ratios, unequivocally confirming the potency of this therapeutic candidate.…”

Section: Discussionmentioning

confidence: 99%

IPH4102, a Humanized KIR3DL2 Antibody with Potent Activity against Cutaneous T-cell Lymphoma

et al. 2014

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Advanced cutaneous T-cell lymphoma (CTCL) remains an unmet medical need, which lacks effective targeted therapies. In this study, we report the development of IPH4102, a humanized monoclonal antibody that targets the immune receptor KIR3DL2, which is widely expressed on CTCL cells but few normal immune cells. Potent antitumor properties of IPH4102 were documented in allogeneic human CTCL cells and a mouse model of KIR3DL2 þ disease. IPH4102 antitumor activity was mediated by antibody-dependent cell cytotoxicity and phagocytosis. IPH4102 improved survival and reduced tumor growth in mice inoculated with KIR3DL2 þ tumors.Ex vivo efficacy was further evaluated in primary S ezary patient cells, sorted natural killer-based autologous assays, and direct spiking into S ezary patient peripheral blood mononuclear cells. In these settings, IPH4102 selectively and efficiently killed primary S ezary cells, including at unfavorable effector-to-target ratios characteristic of unsorted PBMC. Together, our results offer preclinical proof of concept for the clinical development of IPH4102 to treat patients with advanced CTCL. Cancer Res; 74(21); 6060-70. Ó2014 AACR.

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Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies

Cited by 66 publications

References 93 publications

Antibodies reactive to cleaved sites in complement proteins enable highly specific measurement of soluble markers of complement activation

Antibodies reactive to cleaved sites in complement proteins enable highly specific measurement of soluble markers of complement activation

Killing of CLL and NHL cells by rituximab and ofatumumab under limited availability of complement

IPH4102, a Humanized KIR3DL2 Antibody with Potent Activity against Cutaneous T-cell Lymphoma

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