T-cell engager antibodies enable T cells to control HBV infection and to target HBsAg-positive hepatoma in mice

Quitt, Oliver; Luo, Shanshan; Meyer, Marten; Xie, Zhe; Golsaz‐Shirazi, Forough; Loffredo-Verde, Eva; Festag, Julia; Bockmann, Jan-Hendrik; Zhao, Lili; Stadler, Daniela; Chou, Wen-Min; Tedjokusumo, Raindy; Wettengel, Jochen M.; Ko, Chunkyu; Noeßner, Elfriede; Bulbuc, Nadja; Shokri, Fazel; Lüttgau, Sandra; Heikenwälder, Mathias; Bohne, Felix; Moldenhauer, Gerhard; Momburg, Frank; Protzer, Ulrike

doi:10.1016/j.jhep.2021.06.022

Cited by 18 publications

(33 citation statements)

References 27 publications

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“…Similarly, our aCD3 and aCD28 BiMAb exhibited binding to CD4 + and CD8 + T cells. As shown previously (26), we observed two distinct peaks of aEpCAM-aCD28 BiMAb binding to cytotoxic CD8 + T cells, which is consistent with reports that, depending on the donor, CD28 can be variably expressed on CD8 + cells from peripheral blood (30). We next determined the dose response of aCD3 and aCD28 bispecific antibodies driving T cell activation and proliferation in vitro.…”

Section: Enhanced Potency Of T Cell-stimulatory Bimab Through Co-stimulationsupporting

confidence: 90%

“…We studied the characteristics and efficacy of bispecific constructs providing co-stimulatory signals to T cells, that receive an activating signal through BiMAb-mediated crosslinking of the CD3ϵ molecule serving as surrogate for the canonical TCR a/b-MHC-I/II interaction. For bispecific antibodies we utilized a tetravalent (scFv1-Fc KO -scFv2) 2 format that was recently shown by us to be efficacious for the targeting of HBsAg expressed by HBV-infected or HBVenv-transfected hepatoma cells (26). To overcome the issue of Fc receptor engagement and inadvertent bystander T cell activation in the absence of tumor antigen recognition, we introduced mutations to silence the Fc domain in our constructs (26).…”

Section: Discussionmentioning

confidence: 99%

“…The binding moieties of tetravalent BiMAb are V H -(Gly 4 Ser) 3 -V L scFv derived from monoclonal antibodies, anti(a)-EpCAM, HEA125 (US20120213805A1); aHER2 Trastuzumab (PDB:4HJG_B, PDB:4HJG_A); aEGFR Cetuximab (PDB:1YY8_B, PDB:1YY8_A); aCEA, Mfe-23 (PDB:1QOK_A), anti-fibroblast activation protein-a (FAP), BIBH1/Sibrotuzumab, (US20090304718A1); aPD-L1, Avelumab (PDB:5GRJ_H, PDB:5GRJ_L); aCD3ϵ OKT3 (PDB:1SY6_H, PDB:1SY6_L); aCD28, 9.3 (V H GenBank : CAD30987.1, V L GenBank : CAD30986.1). cDNAs coding for the mentioned scFv with tumor antigen specificity were cloned 3' of an hIg-k ER leader sequence followed by a glycine-serine-rich linker ["GSL", GNS(G 4 S) 3 AS] and the hinge-CH2-CH3 domains of hIgG1 (E216-K447) harboring the mutations C220S, E233P, L234A, L235A, DG236, N297Q, K322A, A327G, P329A, A330S, P331S to abolish Fc receptor and complement binding (26). Instead of the stop codon, a StrepTag-II sequence [DPGWSHPQFEKSR] flanked by restriction sites was inserted.…”

Section: Bimab and Tnfl Fusion Protein Cloningmentioning

confidence: 99%

“…Suspension-adapted Freestyle Chinese hamster ovary cells (CHO-S; Invitrogen) were used for transient gene expression as previously described (26,27). CHO-S were routinely cultured in PowerCHO-2 CD (Lonza, Basel, Switzerland), supplemented with 8 mM Ultraglutamine (Lonza) in 500 ml round glass bottles at 37°C, 8% CO 2 and 130 rpm.…”

Section: Production Of Bimab and Tnfl Bifunctional Fusion Proteinsmentioning

confidence: 99%

“…) 2 format recognized tumor-associated antigens with the N-terminal scFv1 and either CD3ϵ or CD28 receptors with the C-terminal scFv2 (26). The Fc portion harbored several mutations to abolish Fc receptor and complement binding.…”

Section: Enhanced Potency Of T Cell-stimulatory Bimab Through Co-stimulationmentioning

confidence: 99%

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Co-Stimulatory Bispecific Antibodies Induce Enhanced T Cell Activation and Tumor Cell Killing in Breast Cancer Models

et al. 2021

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Although T cell-recruiting CD3-binding bispecific antibodies (BiMAb) have been proven to be clinically effective for hematologic malignancies, the success of BiMAb targeting solid tumor-associated antigens (TAA) in carcinomas so far remains poor. We reasoned that provision of co-stimulatory BiMAb in combination with αTAA–αCD3 BiMAb would boost T cell activation and proliferative capacity, and thereby facilitate the targeting of weakly or heterogeneously expressed tumor antigens. Various αTAA–αCD3 and αTAA–αCD28 BiMAb in a tetravalent IgG1-Fc based format have been analyzed, targeting multiple breast cancer antigens including HER2, EGFR, CEA, and EpCAM. Moreover, bifunctional fusion proteins of αTAA–tumor necrosis factor ligand (TNFL) superfamily members including 4-1BBL, OX40L, CD70 and TL1A have been tested. The functional activity of BiMAb was assessed using co-cultures of tumor cell lines and purified T cells in monolayer and tumor spheroid models. Only in the presence of tumor cells, αTAA–αCD3 BiMAb activated T cells and induced cytotoxicity in vitro, indicating a strict dependence on cross-linking. Combination treatment of αTAA–αCD3 BiMAb and co-stimulatory αTAA–αCD28 or αTAA–TNFL fusion proteins drastically enhanced T cell activation in terms of proliferation, activation marker expression, cytokine secretion and tumor cytotoxicity. Furthermore, BiMAb providing co-stimulation were shown to reduce the minimally required dose to achieve T cell activation by at least tenfold. Immuno-suppressive effects of TGF-β and IL-10 on T cell activation and memory cell formation could be overcome by co-stimulation. BiMAb-mediated co-stimulation was further augmented by immune checkpoint-inhibiting antibodies. Effective co-stimulation could be achieved by targeting a second breast cancer antigen, or by targeting fibroblast activation protein (FAP) expressed on another target cell. In tumor spheroids derived from pleural effusions of breast cancer patients, co-stimulatory BiMAb were essential for the activation tumor-infiltrating lymphocytes and cytotoxic anti-tumor responses against breast cancer cells. Taken together we showed that co-stimulation significantly potentiated the tumoricidal activity of T cell-activating BiMAb while preserving the dependence on TAA recognition. This approach could provide for a more localized activation of the immune system with higher efficacy and reduced peripheral toxicities.

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Section: Enhanced Potency Of T Cell-stimulatory Bimab Through Co-stimulationsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Bimab and Tnfl Fusion Protein Cloningmentioning

confidence: 99%

Section: Production Of Bimab and Tnfl Bifunctional Fusion Proteinsmentioning

confidence: 99%

Section: Enhanced Potency Of T Cell-stimulatory Bimab Through Co-stimulationmentioning

confidence: 99%

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Co-Stimulatory Bispecific Antibodies Induce Enhanced T Cell Activation and Tumor Cell Killing in Breast Cancer Models

et al. 2021

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Development and validation of a potential biomarker to improve the assessment of liver fibrosis progression in patients with chronic hepatitis B

Chen

Lang

et al. 2022

Journal of Medical Virology

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We aimed to develop and validate a novel combined score to improve the assessment of liver fibrosis progression in patients with chronic hepatitis B (CHB). In this study, a total of 331 CHB patients from three cohorts who underwent liver biopsy were enrolled, and the Scheuer system was used for liver fibrosis classification. The combined score was derived by principal component analysis of key differentially expressed genes. For significant liver fibrosis (≥S2), the areas under the receiver operating characteristics curves (AUROCs) of the combined score were 0.838, 0.842, and 0.881 in the three cohorts, respectively. And for advanced liver fibrosis (≥S3), the AUROCs were 0.794, 0.801, and 0.901, respectively. Compared with the results of AUROCs for aspartate aminotransferase≥to≥platelet ratio (APRI) and fibrosis index based on four factors (FIB‐4) in the validation cohorts, better clinical diagnostic value for assessing the progression of liver fibrosis was found in the combined score. Additionally, univariate ordered logistic regression analysis indicated that the combined score could serve as a more superior and stable risk factor than APRI and FIB‐4 in the assessment of liver fibrosis. For CHB patients with normal alanine aminotransferase (ALT), our results further emphasized the diagnostic value of the combined score for significant fibrosis (≥S2) and advanced fibrosis (≥S3). Moreover, it was found that patients with the high combined score, who were associated with the advanced fibrosis stage, had higher levels of drug sensitivity and immune checkpoint expression. In conclusion, the novel combined score could serve as a potential biomarker and contribute to improving the assessment of fibrosis stage in CHB patients.

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Rolle der Hepatitis-B-Impfung in der Prävention des hepatozellulären Karzinoms

Dietz-Fricke

Wedemeyer

2021

Onkologe

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Hintergrund Die chronische Hepatitis-B-Infektion stellt einen wesentlichen Risikofaktor für die Entwicklung eines hepatozellulären Karzinoms (HCC) dar. Wenngleich sich die Therapiemöglichkeiten des HCC stetig verbessern, kommt präventiven Maßnahmen eine entscheidende Bedeutung zu. Schlussfolgerung Mit der Hepatitis-B-Impfung steht ein wirksames Mittel zur Verhinderung einer Infektion mit dem Hepatitis-B-Virus (HBV) zur Verfügung. Eine konsequente Impfung führt nicht nur zu einem Rückgang HBsAg-positiver Patienten, sondern bewirkt auch einen Rückgang der HCC-Inzidenz, wie bereits in den 1990er-Jahren in Taiwan gezeigt wurde. Ein suffizienter Schutz vor einer HBV-Infektion verhindert zudem die Infektion mit dem Hepatitis-D-Virus, das mit einem besonders hohen HCC-Risiko behaftet ist. Neuere Ansätze befassen sich auch mit dem therapeutischen Einsatz von Impfstoffen zur Behandlung bereits Infizierter. Wesentlich ist auch das Erkennen bestehender Virushepatitis-Erkrankungen, um Therapien zu beginnen und das HCC-Risiko zu minimieren.

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T-cell engager antibodies enable T cells to control HBV infection and to target HBsAg-positive hepatoma in mice

Cited by 18 publications

References 27 publications

Co-Stimulatory Bispecific Antibodies Induce Enhanced T Cell Activation and Tumor Cell Killing in Breast Cancer Models

Co-Stimulatory Bispecific Antibodies Induce Enhanced T Cell Activation and Tumor Cell Killing in Breast Cancer Models

Development and validation of a potential biomarker to improve the assessment of liver fibrosis progression in patients with chronic hepatitis B

Rolle der Hepatitis-B-Impfung in der Prävention des hepatozellulären Karzinoms

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