Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20+ rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia

Awasthi, Aradhana; Ayello, Janet; Ven, Carmella van de; Elmacken, Mona; Sabulski, Anthony; Barth, Matthew J.; Czuczman, Myron S.; Islam, Humayun; Klein, Christian; Cairo, Mitchell S.

doi:10.1111/bjh.13764

Cited by 87 publications

(69 citation statements)

References 43 publications

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Section: Adcc Response Elicited By Separated Variant Fractionssupporting

confidence: 80%

“…As a control, the experiment was therefore repeated with Rituximab, another therapeutic mAb also targeting the CD20 antigen. Rituximab gave similar results, which correspond well with the ongoing search for possibilities to enhance natural killer cell (NK-cell) activity and ADCC response of Anti-CD20 mAbs [31][32][33] and confirms that the assay in principle works.For both, Erbitux and Herceptin, a considerably lower EC 50 value was measured for the basic charge variant fraction compared to the main and acidic counterparts, which corresponds to a better performance in the assay. For Herceptin the EC 50 value of fraction B was almost 70% lower compared to fraction M. This means that for this fraction, only one third of the protein concentration is necessary in order to achieve similar lysis activity.…”

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confidence: 80%

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Microheterogeneity of therapeutic monoclonal antibodies is governed by changes in the surface charge of the protein

Hintersteiner

Lingg

Janzek

et al. 2016

Biotechnology Journal

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It has previously been shown for individual antibodies, that the microheterogenity pattern can have a significant impact on various key characteristics of the product. The aim of this study was to get a more generalized understanding of the importance of microheterogeneity. For that purpose, the charge variant pattern of various different commercially available therapeutic mAb products was compared using Cation-Exchange Chromatography with linear pH gradient, antigen affinity, Fcreceptor affinity, antibody dependent cellular cytotoxicity (ADCC) and conformational stability. For three of the investigated antibodies, the basic charge variants showed a stronger binding affinity towards FcγRIIIa as well as an increased ADCC response. Differences in the conformational stability of antibody charge variants and the corresponding reference samples could not be detected by differential scanning calorimetry. The different biological properties of the mAb variants are therefore governed by changes in the surface charge of the protein and not by an altered structure. This can help to identify aspects of microheterogeneity that are critical for product quality and can lead to further improvements in the development and production of therapeutic antibody products. Keywords: ADCC · Bio-better · Cation exchange chromatography · Effector functions · FcγRIIIa · Therapeutic mAbsCorrespondence: Prof. Alois Jungbauer, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Muthgasse 18, 1190 Vienna, Austria E-mail: alois.jungbauer@boku.ac.at Abbreviations: ADCC, antibody dependent cellular cytotoxicity; ApHGE, analytical ionexchange chromatography with pH gradient elution; CEX, Cation exchange chromatography; EGFR, epidermal growth factor receptor; mAb, monoclonal antibody; DSC, differential scanning calorimetry; SPR, surface plasmon resonance ants it is still difficult to decide, how precisely a product produced by different methods must match [14][15][16][17][18]. Cation exchange chromatography (CEX) with pH gradient elution has repeatedly been reported as a suitable method for high-resolution separation of antibody variants exhibiting different surface charge characteristics [19][20][21][22]. In this study we used this technique for the analysis and the large-scale separation of several highselling therapeutic antibodies available on the market today, to obtain one acidic (A), one main (M) and one basic (B) charge variant fraction, a methodology previously developed in our group [23,24]. This did not only provide new information on the charge variant pattern of individual monoclonal antibody products, it also gave us the chance to characterize the charge variants found in these antibody products with a wide variety of additional analytical methods and thereby study the overall effect of the presence of charge variants on the stability and biological activity of therapeutic mAbs in general.As starting material, we obtained clinical doses of the seven monoclonal antibodies listed in Table 1, all of w...

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Section: Adcc Response Elicited By Separated Variant Fractionssupporting

confidence: 80%

supporting

confidence: 80%

Microheterogeneity of therapeutic monoclonal antibodies is governed by changes in the surface charge of the protein

Hintersteiner

Lingg

Janzek

et al. 2016

Biotechnology Journal

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“…Furthermore, obinutuzumab was superior in inhibiting growth in NHL xenograft models. 107 Awasthi et al 108 compared obinutuzumab to ritixumab in pre-B-ALL cell lines and found obinutuzumab to be superior in inducing cell death and ADCC. In a pre-B-ALL xenograft model, overall survival was improved with obinutuzumab compared to ritixumab.…”

Section: Future Therapiesmentioning

confidence: 99%

Acute lymphoblastic leukemia: a comprehensive review and 2017 update

2017

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Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone. The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. In adults, 75% of cases develop from precursors of the B-cell lineage, with the remainder of cases consisting of malignant T-cell precursors. Traditionally, risk stratification has been based on clinical factors such age, white blood cell count and response to chemotherapy; however, the identification of recurrent genetic alterations has helped refine individual prognosis and guide management. Despite advances in management, the backbone of therapy remains multi-agent chemotherapy with vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of ALL.

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“…Ofatumumab and obinutuzumab (GA101), the latter demonstrated more active than rituximab even in rituximab-resistant BL cell lines, are other anti-CD20 antibodies deserving further evaluation in BL therapy 117. Other most promising new agents are blinatumomab, a bispecific antibody targeting CD19 and bridging CD19+ BL cells to CD3+ cytotoxic autologous T cells, and inotuzumab ozogamicin, an anti-CD22 monoclonal conjugated to calicheamicin.…”

Section: New Drugs and Treatment Modalitiesmentioning

confidence: 99%

Burkitt lymphoma in adolescents and young adults: management challenges

Dozzo¹,

Carobolante²,

Donisi³

et al. 2016

AHMT

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About one-half of all Burkitt lymphoma (BL) patients are younger than 40 years, and one-third belong to the adolescent and young adult (AYA) subset, defined by an age between 15 and 25–40 years, based on selection criteria used in different reports. BL is an aggressive B-cell neoplasm displaying highly characteristic clinico-diagnostic features, the biologic hallmark of which is a translocation involving immunoglobulin and c-MYC genes. It presents as sporadic, endemic, or epidemic disease. Endemicity is pathogenetically linked to an imbalance of the immune system which occurs in African children infected by malaria parasites and Epstein–Barr virus, while the epidemic form strictly follows the pattern of infection by HIV. BL shows propensity to extranodal involvement of abdominal organs, bone marrow, and central nervous system, and can cause severe metabolic and renal impairment. Nevertheless, BL is highly responsive to specifically designed short-intensive, rotational multiagent chemotherapy programs, empowered by the anti-CD20 monoclonal antibody rituximab. When carefully applied with appropriate supportive measures, these modern programs achieve a cure rate of approximately 90% in the average AYA patient, irrespective of clinical stage, which is the best result achievable in any aggressive lymphoid malignancy to date. The challenges ahead concern the following: optimization of management in underdeveloped countries, with reduction of diagnostic and referral-for-care intervals, and the applicability of currently curative regimens; the development of lower intensity but equally effective treatments for frail or immunocompromised patients at risk of death by complications; the identification of very high-risk patients through positron-emission tomography and minimal residual disease assays; and the assessment in these and the few refractory/relapsed ones of new monoclonals (ofatumumab, blinatumomab, inotuzumab ozogamicin) and new molecules targeting c-MYC and key proliferative steps of B-cell malignancies.

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Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20+ rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia

Cited by 87 publications

References 43 publications

Microheterogeneity of therapeutic monoclonal antibodies is governed by changes in the surface charge of the protein

Microheterogeneity of therapeutic monoclonal antibodies is governed by changes in the surface charge of the protein

Acute lymphoblastic leukemia: a comprehensive review and 2017 update

Burkitt lymphoma in adolescents and young adults: management challenges

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