Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia

Wu, Jingjing; Fu, Jiayin; Zhang, Mingzhi; Liu, Delong

doi:10.1186/s13045-015-0195-4

Cited by 140 publications

(98 citation statements)

References 83 publications

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“…However, as for many other mAbs in antitumor therapy, high doses are needed to obtain clinical efficacy [93]. A successful example for a bispecific antibody is the first-in-class BiTE against CD19/CD3, blinatumomab, which is approved for the treatment of acute lymphoblastic leukemia [94][95][96].…”

Section: Clinical Status Quomentioning

confidence: 99%

mRNA as novel technology for passive immunotherapy

Schlake¹,

Theß²,

Thran³

et al. 2018

Cell. Mol. Life Sci.

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While active immunization elicits a lasting immune response by the body, passive immunotherapy transiently equips the body with exogenously generated immunological effectors in the form of either target-specific antibodies or lymphocytes functionalized with target-specific receptors. In either case, administration or expression of recombinant proteins plays a fundamental role. mRNA prepared by in vitro transcription (IVT) is increasingly appreciated as a drug substance for delivery of recombinant proteins. With its biological role as transient carrier of genetic information translated into protein in the cytoplasm, therapeutic application of mRNA combines several advantages. For example, compared to transfected DNA, mRNA harbors inherent safety features. It is not associated with the risk of inducing genomic changes and potential adverse effects are only temporary due to its transient nature. Compared to the administration of recombinant proteins produced in bioreactors, mRNA allows supplying proteins that are difficult to manufacture and offers extended pharmacokinetics for short-lived proteins. Based on great progress in understanding and manipulating mRNA properties, efficacy data in various models have now demonstrated that IVT mRNA constitutes a potent and flexible platform technology. Starting with an introduction into passive immunotherapy, this review summarizes the current status of IVT mRNA technology and its application to such immunological interventions.

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Section: Clinical Status Quomentioning

confidence: 99%

mRNA as novel technology for passive immunotherapy

Schlake¹,

Theß²,

Thran³

et al. 2018

Cell. Mol. Life Sci.

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“…Novel agents targeting biomarker molecules in lymphocytes are revolutionizing treatment of lymphoid malignancies [25–33]. Since BTK is a critical effector molecule for B cell development and plays a major role in lymphomagenesis, BTK inhibitors have been investigated as potential treatments [11, 34–37].…”

Section: Introductionmentioning

confidence: 99%

Second-generation inhibitors of Bruton tyrosine kinase

et al. 2016

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Bruton tyrosine kinase (BTK) is a critical effector molecule for B cell development and plays a major role in lymphoma genesis. Ibrutinib is the first-generation BTK inhibitor. Ibrutinib has off-target effects on EGFR, ITK, and Tec family kinases, which explains the untoward effects of ibrutinib. Resistance to ibrutinib was also reported. The C481S mutation in the BTK kinase domain was reported to be a major mechanism of resistance to ibrutinib. This review summarizes the clinical development of novel BTK inhibitors, , ONO/GS-4059, and BGB-3111.

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“…Bispecific antibodies are not new (7); however, improvements in engineering have renewed interest in this antibody construct, and there are multiple bispecific agents in clinical development (8). In addition, blinatumomab, a bispecific T-cell engager (BiTE) CD3xCD19 targeting antibody, received an accelerated approval by the FDA for the treatment of a rare form of acute lymphoblastic leukemia (9). Bispecific biotherapeutics bind to both CD3, a T-cell receptor (10), and a target antigen expressed on cancer cells, to recruit and redirect patient T lymphocytes to tumor cells for elimination.…”

Section: Introductionmentioning

confidence: 99%

Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity

Campagne

Delmas

Fouliard

et al. 2018

Clinical Cancer Research

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Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys. Thirty-two animals received multiple escalating doses (100-300-600-1,000 ng/kg/day) via intravenous infusion continuously 4 days a week. The model reflects sequential binding of MGD006 to CD3 and CD123 receptors. Formation of the MGD006/CD3 complex was connected to total T cells undergoing trafficking, whereas the formation of the trimolecular complex results in T-cell activation and clonal expansion. Activated T cells were used to drive the peripheral depletion of CD123-positive cells. Anti-drug antibody development was linked to MGD006 disposition as an elimination pathway. Model validation was tested by predicting the activity of MGD006 in eight monkeys receiving continuous 7-day infusions. MGD006 disposition and total T-cell and CD123-positive cell profiles were well characterized. Anti-drug antibody development led to the suppression of T-cell trafficking but did not systematically abolish CD123-positive cell depletion. Target cell depletion could persist after drug elimination owing to the self-proliferation of activated T cells generated during the first cycles. The model was externally validated with the 7-day infusion dosing schedule. A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacologic activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies. .

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Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia

Cited by 140 publications

References 83 publications

mRNA as novel technology for passive immunotherapy

mRNA as novel technology for passive immunotherapy

Second-generation inhibitors of Bruton tyrosine kinase

Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity

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