Heterodimeric bispecific antibody-derivatives against CD19 and CD16 induce effective antibody-dependent cellular cytotoxicity against B-lymphoid tumor cells

Kellner, Christian; Bruenke, Joerg; Horner, Heike; Schubert, Jöerg; Schwenkert, Michael; Mentz, Kristin; Barbin, Karin; Stein, Christoph; Peipp, Matthias; Stockmeyer, Bernhard; Fey, Georg H.

doi:10.1016/j.canlet.2011.01.020

Cited by 39 publications

(27 citation statements)

References 49 publications

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“…A bsTb ( Figure 3E) with two binding sites for CD19 and one for CD16 showed overall superior properties in comparison to a bispecific bibody (bsBb) with only one binding site each for CD19 and CD16 ( Figure 3F). The bsTb had a 3-fold higher avidity and mediated similar lysis of antigen positive cells at 6-fold lower concentrations than the bsBb [143]. The addition of a second binding site for an antigen on the same tumor cell allowed investigators to reach the objective outlined above.…”

Section: Nk-cell Recruiting Ab-derivatesmentioning

confidence: 99%

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

2012

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Unmodified antibodies (abs) have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors through Fc-engineering. Another way to empower abs is the design of bispecific abs and related fusion proteins allowing a narrower choice of effector cells. Here we review frequently chosen classes of effector cells, as well as common trigger molecules. Natural Killer (NK)-and T-cells are the most investigated populations in therapeutical approaches with bispecific agents until now. Catumaxomab, the first bispecific ab to receive drug approval, targets the tumor antigen Epithelial Cell Adhesion Molecule (EpCAM) and recruits T-cells via a binding site for the cell surface protein CD3. The next generation of recombinant ab-derivatives replaces the broadly reactive Fc-domain by a binding domain for a single selected trigger. Blinatumomab is the first clinically successful member of this class, targeting cancer cells via CD19 and engaging T-cells by CD3. Other investigators have developed related recombinant fusion proteins to recruit effectors, such as NK-cells and macrophages. The first such agents currently in preclinical and clinical development will be discussed.

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Section: Nk-cell Recruiting Ab-derivatesmentioning

confidence: 99%

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

2012

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“…Different tumour types have been targeted by linking these anti-CD16 Fv domains to Fv domains against CD19 (REF. 177) and HLA class II for B cell malignancies 178 , CD30 for Hodgkin's lymphoma 176,179 , epidermal growth factor receptor (EGFR), which is overexpressed in several epithelial cancer types 175 , HER2 (REFS 180,181) for breast cancer, CD33 for AML 182,183 and EPCAM 184 for carcinomas. The in vitro and in vivo efficacy of these optimized proteins in eliciting specific antitumour activity is encouraging and should be further developed in clinical settings.…”

Section: Using Nk Cells For Cancer Therapymentioning

confidence: 99%

NK cells and cancer: you can teach innate cells new tricks

2015

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“…To selectively target gd T cells, we further developed a new antibody construct. Antibody constructs enabling bivalent tumor targeting have been reported to enhance the avidity to the tumor cells and increase the cytolytic activity of bispecific antibodies (37). Thus, we generated a bispecific antibody in the so-called tribody format, allowing bivalent Her2-targeting and monovalent binding to gd T cells (Fig.…”

Section: Comparison Ofmentioning

confidence: 99%

Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

Oberg¹,

Peipp²,

Kellner³

et al. 2014

Cancer Research

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The ability of human gd T cells from healthy donors to kill pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo in immunocompromised mice requires the addition of gd T-cell-stimulating antigens. In this study, we demonstrate that gd T cells isolated from patients with PDAC tumor infiltrates lyse pancreatic tumor cells after selective stimulation with phosphorylated antigens. We determined the absolute numbers of gd T-cell subsets in patient whole blood and applied a real-time cell analyzer to measure their cytotoxic effector function over prolonged time periods. Because phosphorylated antigens did not optimally enhance gd T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vg9 on gd T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced gd T-cell cytotoxicity with the Her2/Vg9 antibody also selectively enhancing release of granzyme B and perforin. Supporting these observations, adoptive transfer of gd T cells with the Her2/Vg9 antibody reduced growth of pancreatic tumors grafted into SCID-Beige immunocompromised mice. Taken together, our results show how bispecific antibodies that selectively recruit gd T cells to tumor antigens expressed by cancer cells illustrate the tractable use of endogenous gd T cells for immunotherapy.

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Heterodimeric bispecific antibody-derivatives against CD19 and CD16 induce effective antibody-dependent cellular cytotoxicity against B-lymphoid tumor cells

Cited by 39 publications

References 49 publications

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

NK cells and cancer: you can teach innate cells new tricks

Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

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