Blinatumomab: First Global Approval

Sanford, Mark

doi:10.1007/s40265-015-0356-3

Cited by 73 publications

(66 citation statements)

References 17 publications

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“…In 2014, blinatumomab, the first BiTE, has been approved by the U.S. Food and Drug Administration for the treatment of Philadelphia chromosomenegative relapsed/refractory B-cell precursor acute lymphocytic leukemia. 9 The BiTE mode of action requires target cell antigens that are selectively expressed in diseased cells to maximize the therapeutic window. Many known MM antigens, including some that are targeted by antibody-based therapies (for example, CD56, CD138, CD74), show overexpression in myeloma cells but are also known to be expressed in normal tissues, 2,4,10,11 thus may not be optimal targets for a T-cell re-direction approach.…”

Section: Introductionmentioning

confidence: 99%

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

et al. 2016

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B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ε (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMApositive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/ refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

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Section: Introductionmentioning

confidence: 99%

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

et al. 2016

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“…5). A major limitation of the earlier TCB molecules was that they induced strong cytokine release and resulted in severe infusion-related reactions, which precluded their systemic administration.…”

Section: Introductionmentioning

confidence: 99%

“…However, by removing the Fc region, protection from catabolism via FcRn recycling was eliminated and this, together with the small molecular size of blinatumomab, leads to fast drug clearance. Indeed, blinatumomab has to be administered via continuous infusion for several weeks (5), an approach which would significantly limit the application of TCBs to the majority of cancer patients. Thus, new TCB molecular formats with comparable or higher efficacy than blinatumomab, but with significantly longer circulatory half-life allowing for systemic administration every few weeks and at the same time avoiding peripheral immune cell activation and cytokine release in the absence to target engagement, are desired.…”

Section: Introductionmentioning

confidence: 99%

A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors

Bacac

Fauti

Sam

et al. 2016

Clinical Cancer Research

289

266

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Purpose: CEA TCB is a novel IgG-based T-cell bispecific (TCB) antibody for the treatment of CEA-expressing solid tumors currently in phase I clinical trials (NCT02324257). Its format incorporates bivalent binding to CEA, a head-to-tail fusion of CEA- and CD3e-binding Fab domains and an engineered Fc region with completely abolished binding to FcγRs and C1q. The study provides novel mechanistic insights into the activity and mode of action of CEA TCB. Experimental Design: CEA TCB activity was characterized on 110 cell lines in vitro and in xenograft tumor models in vivo using NOG mice engrafted with human peripheral blood mononuclear cells. Results: Simultaneous binding of CEA TCB to tumor and T cells leads to formation of immunologic synapses, T-cell activation, secretion of cytotoxic granules, and tumor cell lysis. CEA TCB activity strongly correlates with CEA expression, with higher potency observed in highly CEA-expressing tumor cells and a threshold of approximately 10,000 CEA-binding sites/cell, which allows distinguishing between high- and low-CEA–expressing tumor and primary epithelial cells, respectively. Genetic factors do not affect CEA TCB activity confirming that CEA expression level is the strongest predictor of CEA TCB activity. In vivo, CEA TCB induces regression of CEA-expressing xenograft tumors with variable amounts of immune cell infiltrate, leads to increased frequency of activated T cells, and converts PD-L1 negative into PD-L1–positive tumors. Conclusions: CEA TCB is a novel generation TCB displaying potent antitumor activity; it is efficacious in poorly infiltrated tumors where it increases T-cell infiltration and generates a highly inflamed tumor microenvironment. Clin Cancer Res; 22(13); 3286–97. ©2016 AACR.

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“…+ aggressive B-cell malignancies, and the first such BiTE (Blinatumomab) was recently approved by FDA [64]. Like CAR T cells, BiTEs have the added potential to overcome mutations in signaling pathways that classically lead to resistance.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Targeting B-Cell Maturation Antigen in Multiple Myeloma

2015

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Novel effective immunotherapies are needed for patients with multiple myeloma (MM), since disease recurrence remains a major obstacle. B-cell maturation antigen (BCMA), a cell surface protein universally expressed on malignant plasma cells , has emerged as a very selective antigen to be targeted in novel treatments for MM. We here first review BCMA-related biology, and then highlight the recent clinical development of a novel afucosylated anti-BCMA monoclonal antibody conjugated with monomethyl auristatin F via noncleavable linker (GSK2857916). Chimeric antigen receptor-expressing T cells targeting BCMA may also induce specific and durable anti-MM responses by patients’ own effector cells. Clinical trials testing these two approaches (NCT02064387, NCT02215967) are currently ongoing in relapsed and refractory MM patients.

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Blinatumomab: First Global Approval

Cited by 73 publications

References 17 publications

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors

Targeting B-Cell Maturation Antigen in Multiple Myeloma

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