Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

Coiffier, Bertrand; Leprêtre, Stéphane; Pedersen, Lars Møller; Gadeberg, Ole; Fredriksen, Henrik; Oers, Marinus H. J. van; Wooldridge, James E.; Kłoczko, Janusz; Hołowiecki, Jerzy; Hellmann, Andrzej; Walewski, Jan; Flensburg, Mimi; Petersen, Jørgen; Robak, Tadeusz

doi:10.1182/blood-2007-09-111781

Cited by 356 publications

(232 citation statements)

References 28 publications

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“…However, the reduced CD20 density in CLL as compared with NHL renders translocation in lipid rafts even more necessary, 61,62 and that is what underlies the development of ofatumumab, currently approved in first-line and R/R CLL patients. 63 A complement consumption was observed in CLL patients under RTX, 64,65 contrary to what is observed with OBZ. 56 The results of phase 3, demonstrating the superiority of OBZ over RTX in CLL, highly suggests that CDC is not necessary for anti-CD20 CLL therapy.…”

Section: How To Interpret the Results Of Obz Clinical Trials?contrasting

confidence: 47%

Obinutuzumab: what is there to learn from clinical trials?

Cartron

Watier

2017

Blood

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Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL). Rituximab (RTX) is frequently considered as its "ancestor" and OBZ clinical development was justified by the importance of FcgRIIIAmediated mechanisms in RTX clinical activity. However, RTX differs from OBZ in 2 critical independent properties: being a type I anti-CD20 mAb and not being Fcoptimized. Moreover, the use of a different dosing regimen for RTX and OBZ further complicates any interpretation of clinical results. The results obtained for OBZ in CLL provide new arguments for FcgRIIIAmediated mechanisms when the target antigen is expressed at a low density. Results of OBZ in FL confirm the interest for FcgRIIIA-mediated mechanisms, with some limitations, some of them being possibly due to lack of OBZ-induced complement activation. The situation in diffuse large B-cell lymphoma is deceiving, as the possible gains of activity of OBZ appear to be annihilated by the lack of complement activation. Although RTX was by chance an anti-CD20 mAb with equilibrated pharmacodynamic properties, the reinforcement of some of these properties, which has been done at the expense of complement activation, has conferred an advantage in some B-cell disorders while restricting OBZ indications. The OBZ story nicely demonstrates that the future of naked mAbs is to design agents with optimized and tailored properties, and that this must be done step by step, with a full clinical validation. (Blood. 2017;130(5):581-589) Introduction Obinutuzumab (OBZ) is the first recombinant type II anti-CD20 and immunoglobulin G1 (IgG1) Fc-optimized monoclonal antibody (mAb) approved by the US Food and Drug Administration (FDA) and European Medicines Agency. It is currently labeled in first-line chronic lymphocytic leukemia (CLL) patients in association with chlorambucil, and in combination with bendamustine followed by OBZ monotherapy for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab (RTX)-containing regimen. RTX was the first anti-CD20 mAb approved and largely contributed to establish the therapeutic value of anti-CD20 strategies in almost all CD201 malignancies. Experimental studies demonstrated that RTX is able to induce CD20 1 cell death by several mechanisms.1 RTX is sometimes presented as the "ancestor" of OBZ. First of all, OBZ is in no way a RTX biosimilar: not only are their variable domains totally different but also, in addition, RTX does not recognize the same CD20 epitope as OBZ and is a human IgG1 non-Fc-optimized antibody, 2 characteristics independent from each other and having functional and pharmacological consequences that need to be taken into consideration when trying to compare the 2 drugs. OBZ development was largely based on the presumed importance of FcgRIIIA-mediated mechanisms in RTX clinical activity, this being mainly supported by the influ...

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Section: How To Interpret the Results Of Obz Clinical Trials?contrasting

confidence: 47%

Obinutuzumab: what is there to learn from clinical trials?

Cartron

Watier

2017

Blood

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“…18 A total of 33 patients were included. The majority (27/33) of patients received a total of four doses administered once weekly; an initial dose of 500 mg was followed by three 2,000 mg doses.…”

Section: Phase 1/2mentioning

confidence: 99%

Ofatumumab

Zhang

2009

mAbs

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Ofatumumab is an anti-CD20 IgG1κ human monoclonal antibody that is being considered by the US Food and Drug Administration and the European Medicines Agency for marketing approval as a treatment for chronic lymphocytic leukemia. The mAb is also being studied as a treatment for lymphoma, rheumatoid arthritis and multiple sclerosis. The candidate targets the same antigen as rituximab, but ofatumumab binds a novel, membrane-proximal epitope, and dissociates from its target at a slower rate compared to rituximab. Ofatumumab might be approved in the US by August 2009.

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“…3 Phase I/II trials showed that ofatumumab as a single agent is well tolerated with an overall response rate of approximately 50% in patients with relapsed/refractory CLL, including those refractory to fludarabine and alemtuzumab. 4 In October 2009, ofatumumab was, therefore, approved by the Food and Drug Administration for the treatment of fludarabine and alemtuzumab double-refractory CLL.…”

Section: Introductionmentioning

confidence: 99%

Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells

et al. 2013

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The antitumor activity of monoclonal antibodies in the treatment of chronic lymphocytic leukemia is mediated mainly by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Unfortunately, the efficacy of complement-dependent cytotoxicity is strongly restricted due to the expression and acquisition of regulators of complement activation by lymphocytic leukemia cells. Whereas the role of membrane regulators of complement activation, such as CD55 and CD59, has been investigated in detail in chronic lymphocytic leukemia, the involvement of soluble regulators of complement activation, such as complement factor H, has not yet been reported. Propidium iodide staining was performed to investigate the efficacy of ofatumumab and factor H-derived shortconsensus-repeat 18-20 in the induction of complement-dependent cytotoxicity on primary chronic lymphocytic leukemia cells from 20 patients. Deposition of complement C3 fragments was monitored by western blot analysis. Expression of CD20, CD55 or CD59 was determined by FACS analysis. Replacement of factor H with short consensus repeat 18-20 significantly increased the susceptibility of primary chronic lymphocytic leukemia cells to ofatumumab-induced complement-dependent cytotoxicity. More importantly, addition of short-consensus-repeat 18-20 was able to overcome complement-resistance occurring during treatment with ofatumumab alone. Use of short consensus repeat 18-20 is likely to prolong the turnover time of active C3b fragments generated on the target cells following ofatumumab-induced complement activation, thereby improving specific killing of chronic lymphocytic leukemia cells by complement-dependent cytotoxicity. The relative contribution of factor H to the protection of chronic lymphocytic leukemia cells against complement-dependent cytotoxicity was comparable to that of CD55. Our data suggest that, by abrogating factor H function, short consensus repeat 18-20 may provide a novel approach that improves the complement-dependent efficacy of therapeutic monoclonal antibodies.

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Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

Cited by 356 publications

References 28 publications

Obinutuzumab: what is there to learn from clinical trials?

Obinutuzumab: what is there to learn from clinical trials?

Ofatumumab

Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells

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