Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Feb;103(2):e78-e81.
doi: 10.3324/haematol.2017.178996. Epub 2017 Oct 27.

GA101 P329GLALA, a variant of obinutuzumab with abolished ADCC, ADCP and CDC function but retained cell death induction, is as efficient as rituximab in B-cell depletion and antitumor activity

Sylvia Herter  1 , Frank Herting  2 , Gunter Muth  2 , Erwin van Puijenbroek  1 , Tilman Schlothauer  2 , Claudia Ferrara  1 , Kevin Brady  3 , Sabine Lang  1 , Marina Bacac  1 , Ekkehard Mössner  1 , Pablo Umana  1 , Christian Klein  4
Affiliations

GA101 P329GLALA, a variant of obinutuzumab with abolished ADCC, ADCP and CDC function but retained cell death induction, is as efficient as rituximab in B-cell depletion and antitumor activity

Sylvia Herter et al. Haematologica. 2018 Feb.
No abstract available

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
In vitro characterization of GA101, rituximab and effector inactive variants. A: P329GLALA mutations do not affect direct cell death. Z-138 cells were incubated for 22 h in the presence of CD20 antibodies as indicated. Afterwards, cells were stained with Annexin V FLUOS and PI and analysed by flow cytometry. B: P329GLALA mutations abolish CDC induction. SU-DHL-4 or Z-138 cells were incubated with rabbit complement in the presence of CD20 antibodies as indicated. CDC was calculated based on LDH release after 2 h (left) or AlamarBlue readout after 22 h (right). Average triplicates of both cell lines shown. C: P329GLALA mutations abolish ADCC induction and NK cell activation, SU-DHL-4 (right) or Z-138 (left) cells were incubated with human PBMCs (E:T 25:1) for 4 h in the presence of CD20 antibodies as indicated. Top: ADCC was calculated based on LDH release, bottom: Degranulation of CD3−CD56+ NK cells was analyzed by flow cytometry measuring surface CD107a expression levels. Triplicates (LDH: Average triplicates) for 2 donors per target cell line shown.
Figure 2
Figure 2
A. Immune effector-inactive GA101-P329GLALA mediates significant whole blood B-cell depletion. B-cell depletion in whole blood of healthy donors was determined after 20h incubation in the presence of CD20 antibodies as indicated by flow cytometry. Summary results (average triplicates) from two different blood donors are shown. B: Absence of cytokine release for GA101-P329GLALA. Cytokine release upon incubation of human whole blood with CD20 antibodies was measured after 20h incubation performing a CBA analysis of the plasma. Mean fold change of cytokine release compared to untreated blood shown (N = 3).
Figure 3.
Figure 3.
Immune effector-inactive GA101-P329GLALA mediates comparable anti-tumoral efficacy compared to rituximab in s.c. SU-DHL4 xenograft model in Scid beige mice. Scid beige mice bearing established 300 mm3 s.c. SU-DHL4 tumors were treated with the indicated antibodies (30 mg/kg, q7d×4; IP). Tumor size was determined at the indicated time points, and tumor growth inhibition and non parametric treatment-control ratios (np TCR) with 95% confidence interval as well as the number of tumor-free animals at study termination on Day 49 were determined.
See this image and copyright information in PMC

References

    1. Mossner E, Brunker P, Moser S, et al. Increasing the efficacy of cd20 antibody therapy through the engineering of a new type ii anti-cd20 antibody with enhanced direct and immune effector cell-mediated b-cell cytotoxicity. Blood. 2010;115(22):4393–4402. - PMC - PubMed
    1. Lee HZ, Miller BW, Kwitkowski VE, et al. U.S. Food and drug administration approval: Obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia. Clin Cancer Res. 2014;20(15):3902–3907. - PubMed
    1. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with cll and coexisting conditions. N Engl J Med. 2014; 370(12):1101–1110. - PubMed
    1. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081–1093. - PubMed
    1. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017;377(14):1331–1344. - PubMed

MeSH terms