Clinical overview of anti-CD19 BiTE® and ex vivo data from anti-CD33 BiTE® as examples for retargeting T cells in hematologic malignancies

Zugmaier, Gerhard; Klinger, Mark; Шмидт, М В; Субклеве, М.; Киргизов, К. И.; Шаманская, Т. В.

doi:10.17650/2311-1267-2016-3-2-18-30

Cited by 7 publications

(10 citation statements)

References 24 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Construction of a prototypical bispecific T-cell engager (BiTE®) antibody and mechanism of action. (Reprinted with permission fromZugmaier et al [2015]. )…”

mentioning

confidence: 99%

The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia

Benjamin

Stein

2016

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

Adults with relapsed/refractory B-acute lymphoblastic leukemia (ALL) have a complete remission (CR) rate of 20-45% and median overall survival of 3-9 months, depending on the duration of the first remission and number of lines of salvage therapy. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative option for adult patients with relapsed/refractory ALL, and achievement of CR is a crucial step before alloHSCT. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct with dual specificity for CD19 and CD3, simultaneously binding CD3-positive cytotoxic T cells and CD19-positive B cells, resulting in T-cell-mediated serial lysis of normal and malignant B cells. It recently gained accelerated approval by the US Food and Drug Administration (FDA) for the treatment of relapsed/refractory Philadelphia chromosome-negative ALL, based on a large phase II trial of 189 adults with relapsed/refractory B-ALL, which showed a CR/CRh (CR with partial hematologic recovery) of 43% after two cycles of treatment. Toxicities include cytokine-release syndrome (CRS) and neurologic events (encephalopathy, aphasia, and seizure). CRS can be alleviated by step-up dosing and dexamethasone, without affecting the cytotoxic effect of blinatumomab. The cause of neurologic toxicity is unclear but is also observed with other T-cell therapies and may relate to variable expression of CD19 within the brain. This review encompasses the preclinical rationale of using the BITE® class of compounds (blinatumomab being the only one that is FDA approved), with clinical data using blinatumomab in the relapsed/refractory setting (pediatrics and adults), the minimal residual disease setting (adults), as well as Philadelphia chromosome-positive ALL. The review also examines the main adverse events: their prevention, recognition, and management; possible mechanisms of resistance; causes of relapse. It also summarizes future trials evaluating the drug earlier in the treatment course to improve activity.

show abstract

“…Construction of a prototypical bispecific T-cell engager (BiTE®) antibody and mechanism of action. (Reprinted with permission fromZugmaier et al [2015]. )…”

mentioning

confidence: 99%

The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia

Benjamin

Stein

2016

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

show abstract

“…Several BsAbs presently in clinical development are designed to redirect T cells to tumor cells. 26,27 In addition to T cells, other immune cells, such as macrophages, monocytes, granulocytes, and NK cells, can also exert tumorkilling effects. BsAbs with a non-IgG-like format are smaller in size, leading to enhanced tissue penetration, while BsAbs with an IgG-like format usually have a longer serum half-life due to their larger size and FcRn-mediated recycling.…”

Section: Discussionmentioning

confidence: 99%

CD89-mediated recruitment of macrophages via a bispecific antibody enhances anti-tumor efficacy

et al. 2017

OncoImmunology

View full text Add to dashboard Cite

Since tumors are often infiltrated by macrophages, it would be advantageous to turn these types of cells into cytotoxic effector cells. Here, we have designed a novel bispecific antibody (BsAb) that targets both tumor antigen (CD20) and the FcαRI receptor (CD89). This antibody could be used to lyse tumors by connecting tumor cells to CD89-expressing immune effector cells such as macrophages and neutrophils. Previously there were very limited attempts to exploit FcαRI-expressing cells as effector cells for tumor cell-killing, largely due to the lack of an appropriate model, since mice do not express a human CD89 homolog. In this study, we used a transgenic mouse strain with specific expression of CD89 on macrophages and monocytes. In this transgenic mouse model, the CD89 bispecific antibody showed significant anti-tumor activities, demonstrating that bispecific antibodies can redirect macrophages, including M2 macrophages, to mediate additional effector function in the tumor microenvironment. This approach realized the full potential of the innate immune system and could be applied to other tumor-associated antigens especially the solid tumors, thus has potential to translate into clinical benefits in human cancers.

show abstract

“…The cytolytic synapses formed by BiTE antibodies are essentially identical in structure and composition to typical synapses created by matching T‐cell receptor, peptide antigen, and MHC class I molecules . Following synapse formation, polyclonal T‐cell activation and expansion results in target cell destruction through the action of lytic granules and cytokines released in the synapse, without need for antigen recognition by the T‐cell receptor . Due to its small size (approximately 54 kDa), the half‐life of blinatumomab is about 1.25 hours and, as a result, it is administered daily by continuous intravenous infusion at a constant flow rate (after an initial dose escalation) in repeated four‐week cycles .…”

Section: Cd3 Bispecific Antibody Formatsmentioning

confidence: 99%

Bispecific Antibodies in the Treatment of Hematologic Malignancies

Duell

Lammers

Djuretic

et al. 2019

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single‐agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single‐agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients.

show abstract

Clinical overview of anti-CD19 BiTE® and ex vivo data from anti-CD33 BiTE® as examples for retargeting T cells in hematologic malignancies

Cited by 7 publications

References 24 publications

The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia

The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia

CD89-mediated recruitment of macrophages via a bispecific antibody enhances anti-tumor efficacy

Bispecific Antibodies in the Treatment of Hematologic Malignancies

Contact Info

Product

Resources

About