GA101 induces NK-cell activation and antibody-dependent cellular cytotoxicity more effectively than rituximab when complement is present

Kern, Delila J.; James, Britnie R.; Blackwell, Sue; Gassner, Christian; Klein, Christian; Weiner, George J.

doi:10.3109/10428194.2013.781169

Cited by 59 publications

(46 citation statements)

References 27 publications

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“…We observed that ofatumumab was clearly superior to rituximab at low antibody concentrations, whereas at higher concentrations (>50 ng/mL) its Bcell depletion properties declined. It is thought that both ofatumumab and rituximab mediate tumor cell killing via ADCC until saturation and that at higher concentrations complement fixation occurs, which may interfere with ADCC resulting in a "bell-shaped" curve (32,33). Therefore, the decreased B-cell depletion observed with ofatumumab at high antibody concentrations may be attributable to the reported increased affinity of ofatumumab for complement factors (10), although in the current study, we did not detect any significant difference in complement binding and CDC activity in vitro.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Activity of the Type II CD20 Antibody GA101 (Obinutuzumab) Compared with Rituximab and Ofatumumab In Vitro and in Xenograft Models

Herter

Herting

Mundigl

et al. 2013

Molecular Cancer Therapeutics

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303

252

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We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cellmediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation. Mol Cancer Ther; 12(10); 2031-42. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Preclinical Activity of the Type II CD20 Antibody GA101 (Obinutuzumab) Compared with Rituximab and Ofatumumab In Vitro and in Xenograft Models

Herter

Herting

Mundigl

et al. 2013

Molecular Cancer Therapeutics

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303

252

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“…1B), resulting in low levels of CDC [12,13,23]. CDC induction by obinutuzumab is >10-to 100-fold less than with the type I mAbs rituximab and ofatumumab [24], resulting in a further-increased capacity to bind and activate natural killer (NK) cells in the presence of complement [25]. FccRIIb-mediated CD20 internalization has been implicated in reduced rituximab efficacy.…”

Section: Introductionmentioning

confidence: 98%

Obinutuzumab in hematologic malignancies: Lessons learned to date

Illidge

Klein

Sehn

et al. 2015

Cancer Treatment Reviews

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The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies.

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“…72 In addition, NK-mediated ADCC capacity of the glycoengineered mAb obinutuzumab (GA101), having a decreased ability to fix complement compared with rituximab, was not affected in the presence of complement. 73 To confirm those findings in vivo, a murine anti-idiotype mAb directed against murine 38C13 B cell lymphomas was used to show that serum blocks murine NK cell activation. In the syngeneic mouse model, mice depleted of complement showed an improved antitumor effect.…”

Section: The Role Of Complement In Ab Immunotherapymentioning

confidence: 99%

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

Meyer

Leusen

Boross

2014

mAbs

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GA101 induces NK-cell activation and antibody-dependent cellular cytotoxicity more effectively than rituximab when complement is present

Cited by 59 publications

References 27 publications

Preclinical Activity of the Type II CD20 Antibody GA101 (Obinutuzumab) Compared with Rituximab and Ofatumumab In Vitro and in Xenograft Models

Preclinical Activity of the Type II CD20 Antibody GA101 (Obinutuzumab) Compared with Rituximab and Ofatumumab In Vitro and in Xenograft Models

Obinutuzumab in hematologic malignancies: Lessons learned to date

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

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