The Role of Obinutuzumab in the Management of Follicular Lymphoma

O’Nions, Jenny; Townsend, William

doi:10.2217/fon-2019-0193

Cited by 7 publications

(3 citation statements)

References 61 publications

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“…Obinutuzumab (Gazyvaro ® , Gazyva ® ) is a humanized and glycoengineered monoclonal IgG 1 antibody against the CD20 type II epitope [ 2 ]. It is mainly applied for the treatment of chronic lymphatic leukemia in combination with chlorambucil, and follicular lymphoma in combination with bendamustine [ 3 , 4 , 5 ]. The type II mechanism of action together with glycoengineering of obinutuzumab results in augmented direct signaling-induced cell death as well as antibody-dependent cell-medicated cytotoxicity (ADCC) and phagocytosis (ADCP) while complement-dependent cytotoxicity (CDC) is diminished [ 4 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Panjideh

Niesler

Weng

et al. 2022

Toxins

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Immunotoxins do not only bind to cancer-specific receptors to mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. The plant glycoside SO1861 was previously reported to enhance the endolysosomal escape of antibody-toxin conjugates in non-hematopoietic cells, thus increasing their cytotoxicity manifold. Here we tested this technology for the first time in a lymphoma in vivo model. First, the therapeutic CD20 antibody obinutuzumab was chemically conjugated to the ribosome-inactivating protein dianthin. The cytotoxicity of obinutuzumab-dianthin (ObiDi) was evaluated on human B-lymphocyte Burkitt’s lymphoma Raji cells and compared to human T-cell leukemia off-target Jurkat cells. When tested in combination with SO1861, the cytotoxicity for target cells was 131-fold greater than for off-target cells. In vivo imaging in a xenograft model of B-cell lymphoma in mice revealed that ObiDi/SO1861 efficiently prevents tumor growth (51.4% response rate) compared to the monotherapy with ObiDi (25.9%) and non-conjugated obinutuzumab (20.7%). The reduction of tumor volume and overall survival was also improved. Taken together, our results substantially contribute to the development of a combination therapy with SO1861 as a platform technology to enhance the efficacy of therapeutic antibody-toxin conjugates in lymphoma and leukemia.

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Section: Introductionmentioning

confidence: 99%

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Panjideh

Niesler

Weng

et al. 2022

Toxins

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“…Modification of Fc fragment of mAb to improve its binding affinity to FcγRIIIa proved to stimulate enhanced ADCC and CDC against lymphoma and leukemia cells as compared to unmodified RTX [64]. Fc-engineering strategy has been also employed in the generation of anti-CD20 mAb-obinutuzumab (OBI) currently registered for the treatment of CLL and FL [65]. OBI demonstrated markedly enhanced binding affinity to FcγRIIIa and dramatically improved potency of ADCC in comparison to RTX.…”

Section: Solutions To Improve Adcc Efficacy 231 Fc Receptor Engineeringmentioning

confidence: 99%

Molecular Aspects of Resistance to Immunotherapies—Advances in Understanding and Management of Diffuse Large B-Cell Lymphoma

Kusowska

Kubacz

Krawczyk

et al. 2022

IJMS

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Despite the unquestionable success achieved by rituximab-based regimens in the management of diffuse large B-cell lymphoma (DLBCL), the high incidence of relapsed/refractory disease still remains a challenge. The widespread clinical use of chemo-immunotherapy demonstrated that it invariably leads to the induction of resistance; however, the molecular mechanisms underlying this phenomenon remain unclear. Rituximab-mediated therapeutic effect primarily relies on complement-dependent cytotoxicity and antibody-dependent cell cytotoxicity, and their outcome is often compromised following the development of resistance. Factors involved include inherent genetic characteristics and rituximab-induced changes in effectors cells, the role of ligand/receptor interactions between target and effector cells, and the tumor microenvironment. This review focuses on summarizing the emerging advances in the understanding of the molecular basis responsible for the resistance induced by various forms of immunotherapy used in DLBCL. We outline available models of resistance and delineate solutions that may improve the efficacy of standard therapeutic protocols, which might be essential for the rational design of novel therapeutic regimens.

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“…This important therapeutic notion has led to the development of Fc glyco-engineered antibodies, especially low-fucosylated antibodies, for increasing CD16 affinity, for improving antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and for compensating the inhibitory effect of the high amount of multi-specific immunoglobulins G (IgGs) from serum of patients [ 18 ]. Based on this technology, the anti-CD20 antibody obinutuzumab was the first glyco-engineered antibody approved for chronic lymphocytic leukemia and follicular lymphoma treatment [ 19 , 20 ]. Regarding solid tumors, imgatuzumab, one of the most advanced glyco-engineered antibody, showed promising results in epidermal growth factor receptor (EGFR)-positive solid tumors [ 21 ], in head and neck squamous cell carcinoma and in colorectal cancer showing complete and partial response in Phase I and II studies [ 22 , 23 ], especially with tumors highly infiltrated by immune cells at baseline.…”

Section: Introductionmentioning

confidence: 99%

Murlentamab, a Low Fucosylated Anti-Müllerian Hormone Type II Receptor (AMHRII) Antibody, Exhibits Anti-Tumor Activity through Tumor-Associated Macrophage Reprogrammation and T Cell Activation

Prat

Salon

Allain

et al. 2021

Cancers

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AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but is also re-expressed in gynecologic cancers. Hence, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody currently in clinical trial. Low-fucosylated antibodies are known to increase the antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) potency of effector cells, but some preliminary results suggest a more global murlentamab-dependent activation of the immune system. In this context, we demonstrate here that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells, in the presence of unstimulated- or tumor-associated macrophage (TAM)-like macrophages, significantly promotes macrophage-mediated ADCC and shifts the whole microenvironment towards a pro-inflammatory and anti-tumoral status, thus triggering anti-tumor activity. We also report that murlentamab orients both unstimulated- and TAM-like macrophages to an M1-like phenotype characterized by a strong expression of co-stimulation markers, pro-inflammatory cytokines and chemokines, favoring T cell recruitment and activation. Moreover, we show that murlentamab treatment shifts CD4+ Th1/Th2 balance towards a Th1 response and activates CD8+ T cells. Altogether, these results suggest that murlentamab, through naïve macrophage orientation and TAM reprogrammation, stimulates the anti-tumor adaptive immune response. Those mechanisms might contribute to the sustained clinical benefit observed in advanced cancer patients treated with murlentamab. Finally, the enhanced murlentamab activity in combination with pembrolizumab opens new therapeutic perspectives.

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The Role of Obinutuzumab in the Management of Follicular Lymphoma

Cited by 7 publications

References 61 publications

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

Molecular Aspects of Resistance to Immunotherapies—Advances in Understanding and Management of Diffuse Large B-Cell Lymphoma

Murlentamab, a Low Fucosylated Anti-Müllerian Hormone Type II Receptor (AMHRII) Antibody, Exhibits Anti-Tumor Activity through Tumor-Associated Macrophage Reprogrammation and T Cell Activation

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