CD20‐Specific Immunoligands Engaging NKG2D Enhance γδ T Cell‐Mediated Lysis of Lymphoma Cells

Peipp, Matthias; Wesch, Daniela; Oberg, Hans‐Heinrich; Lutz, Sebastian; Muskulus, Anja; Winkel, Jan G. J. van de; Parren, Paul W.H.I.; Burger, Renate; Humpe, Andreas; Kabelitz, Dieter; Gramatzki, Martin; Kellner, Christian

doi:10.1111/sji.12581

Cited by 22 publications

(16 citation statements)

References 51 publications

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“…Redirection of immune cells towards diseased cells are termed as effector cells that can comprise other cells beyond T cells and include NK cells, macrophages, neutrophils, monocytes, and granulocytes [396,543] to facilitate specific killing of tumor cells. Each of the effector cells express different types of activating receptors, and a specific population can be recruited by carefully selecting the targeted trigger receptor [544,545]. Redirected cytotoxic activity has been shown, with bispecific antibodies recruiting all effector cells, including macrophages [546].…”

Section: Considerations For Selectionmentioning

confidence: 99%

Antibody Structure and Function: The Basis for Engineering Therapeutics

et al. 2019

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Antibodies and antibody-derived macromolecules have established themselves as the mainstay in protein-based therapeutic molecules (biologics). Our knowledge of the structure–function relationships of antibodies provides a platform for protein engineering that has been exploited to generate a wide range of biologics for a host of therapeutic indications. In this review, our basic understanding of the antibody structure is described along with how that knowledge has leveraged the engineering of antibody and antibody-related therapeutics having the appropriate antigen affinity, effector function, and biophysical properties. The platforms examined include the development of antibodies, antibody fragments, bispecific antibody, and antibody fusion products, whose efficacy and manufacturability can be improved via humanization, affinity modulation, and stability enhancement. We also review the design and selection of binding arms, and avidity modulation. Different strategies of preparing bispecific and multispecific molecules for an array of therapeutic applications are included.

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Section: Considerations For Selectionmentioning

confidence: 99%

Antibody Structure and Function: The Basis for Engineering Therapeutics

et al. 2019

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“…Activating receptors of NK cells such as NKG2D , NKp30 , and NKp80 have been harnessed in tumor immunotherapy. Recombinant fusion proteins enhancing NK‐cell cytotoxicity to malignant cells through NKG2D ligands such as MICA and ULBPs have been reported . We established a chimeric NKG2D reporter system that enables us to monitor the activation of NKG2D signaling once engaged by its ligands.…”

Section: Discussionmentioning

confidence: 99%

“…NKG2D is an activating receptor expressing on NK cells and different subtypes of T cells. It is reported that the NKG2D ligands‐based immunotherapeutic proteins have been used to mobilized NK cells, γδT to eliminate breast cancer , hepatocarcinoma , or B lymphoma cells . It may be necessary for the fusion protein to bind to tumor cells before it binds to, activates, and exhausts NKG2D signaling.…”

Section: Discussionmentioning

confidence: 99%

NK cell‐mediated anti‐leukemia cytotoxicity is enhanced using a NKG2D ligand MICA and anti‐CD20 scfv chimeric protein

et al. 2018

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NK cells are important innate cytotoxic lymphocytes that have potential in treatment of leukemia. Engagement of NKG2D receptor on NK cells enhances the target cytotoxicity. Here, we produced a fusion protein consisting of the extracellular domain of the NKG2D ligand MICA and the anti-CD20 single-chain variable fragment (scfv). This recombinant protein is capable of binding both NK cells and CD20 tumor cells. Using a human NKG2D reporter cell system we developed, we showed that this fusion protein could decorate CD20 tumor cells with MICA extracellular domain and activate NK through NKG2D. We further demonstrated that this protein could specifically induce the ability of a NK cell line (NKL) and primary NK cells to lyse CD20 leukemia cells. Moreover, we found that downregulation of surface HLA class I expression in the target cells improved NKL-mediated killing. Our results demonstrated that this recombinant protein specifically lyses leukemia cells by NK cells, which may lead to development of a novel strategy for treating leukemia and other tumors.

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“…Wesch and colleagues ( 97 ) developed recombinant immunoligands consisting of a CD20 single-chain variable fragment (scFv) linked to MICA or ULBP2 and found that both constructs promoted the cytotoxic activity of ex vivo -expanded γδ T cells (containing both Vδ1 and Vδ2 T cells) against CD20-positive lymphoma cells. Importantly, these two immunoligands mediated the killing of chronic lymphocytic leukemia cells isolated from patients by γδ T cells, which was even enhanced by the PAg BrHPP.…”

Section: Can We Improve γδ T Cell-based Tumor Immunotherapy?mentioning

confidence: 99%

Current Advances in γδ T Cell-Based Tumor Immunotherapy

et al. 2017

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γδ T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of γδ T cells: those that express Vδ1 gene, paired with different Vγ elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, γδ T cells expressing the Vδ2 gene paired with the Vγ9 chain are the predominant (50–90%) γδ T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote γδ T cell activation. γδ T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that αβ T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-γ and tumor necrosis factor-α and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of γδ T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of γδ T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded γδ T cells, particularly the Vγ9Vδ2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that γδ T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the γδ T cell-based immunotherapy of cancer.

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CD20‐Specific Immunoligands Engaging NKG2D Enhance γδ T Cell‐Mediated Lysis of Lymphoma Cells

Cited by 22 publications

References 51 publications

Antibody Structure and Function: The Basis for Engineering Therapeutics

Antibody Structure and Function: The Basis for Engineering Therapeutics

NK cell‐mediated anti‐leukemia cytotoxicity is enhanced using a NKG2D ligand MICA and anti‐CD20 scfv chimeric protein

Current Advances in γδ T Cell-Based Tumor Immunotherapy

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