Recombinant CD95-Fc (APG101) prevents graft-versus-host disease in mice without disabling antitumor cytotoxicity and T-cell functions

Hartmann, Natalie; Messmann, Joanna J.; Leithäuser, Frank; Weiswange, Maxi; Kluge, Michael; Fricke, Harald; Debatin, Klaus‐Michael; Strauß, Gudrun

doi:10.1182/blood-2012-04-423392

Cited by 8 publications

(5 citation statements)

References 52 publications

(63 reference statements)

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“…It should be noted that, in the present study, which included low and intermediate risk patients with MDS, the proportion of fatal infections was lower in patients responding to asunercept. With regard to immunologic effects, asunercept was found to prevent the development of graft-versus-host disease, while preserving graft-versus-leukemia effects in murine transplant models [36]. Consequently, treatment with asunercept probably involves immunosuppressive, or rather immunomodulating effects.…”

Section: Discussionmentioning

confidence: 99%

“…Categorical and continuous variables of patient characteristics were compared using Fisher's exact test and the Mann-Whitney test, respectively. The comparison of the transfusion burden (treatment phase [week 1-12] versus second post-treatment phase [week [25][26][27][28][29][30][31][32][33][34][35][36][37]) was performed by using a matched-pairs Wilcoxon signed rank test.…”

Section: Discussionmentioning

confidence: 99%

“…Except for median serum C-reactive protein (CRP) level at baseline which was slightly higher in non-responding patients (6.1 versus 2.6 mg/L, p = 0.026), no differences in disease and treatment characteristics between "responders" (n = 9) and "non-responders" (n = 10) were observed ( Table 1). [25][26][27][28][29][30][31][32][33][34][35][36][37] in responding versus non-responding patients (sd, standard deviation; ** p < 0.01). (B) In retrospective post hoc analysis, response to asunercept was associated with improved overall survival (OS, logrank p = 0.039).…”

Section: Response To Asunercept Treatmentmentioning

confidence: 99%

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Clinical Response to the CD95-Ligand Inhibitor Asunercept Is Defined by a Pro-Inflammatory Serum Cytokine Profile

Radujkovic

Boch

Nolte

et al. 2020

Cancers

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Asunercept (APG101) is a well-tolerated CD95-ligand inhibitor that showed promising efficacy in a prospective, single-arm phase I study in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome (MDS). In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response, in order to propose a hypothetical responder serum profile. After an updated median follow-up of 54 months (range 7–65), response to asunercept was associated with improved overall survival (at 3-years: 67% [95%CI 36–97] versus 13% [95%CI 0–36] in responders versus non-responders, respectively). Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept (area under the receiver operating characteristic curve 0.79–0.82). Furthermore, non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Although prospective validation is required, our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk MDS patients most likely to benefit from asunercept treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Response To Asunercept Treatmentmentioning

confidence: 99%

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Clinical Response to the CD95-Ligand Inhibitor Asunercept Is Defined by a Pro-Inflammatory Serum Cytokine Profile

Radujkovic

Boch

Nolte

et al. 2020

Cancers

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“…Since the initial observation on the prevention of cytotoxic T lymphocytes (CTL)-induced fulminant hepatitis by mouse FasRECD-human IgG1 Fc domain chimera protein in mice [193], effective engineered hFasRECD molecules have been investigated for suppressing harmful biological functions caused by hFasL.So far, two clinically important strategies, which can contribute to the treatment of serious diseases, have been devised. One is the abrogation of excessive apoptosis induction caused by hFasL in CTL [194] and the other is inhibition of unwanted non-apoptotic signaling processes, proliferation and migration, mediated by hFasR on the surface of malignant tumor cells displaying resistance to normal apoptosis [195]. Both strategies have been proved to be efficiently attained by the divalent fusion protein of hFasRECD connected to human IgG1 Fc domain (hFasRECD-Fc), which was named APG101 by the manufacturer in clinical trials.…”

Section: Great Potential In Medical Applications As Protein Therapeuticsmentioning

confidence: 99%

Untitled

2014

Integr Mol Med

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A variety of proteins with potential for medical applications contain disulfide-bridges. In this review, the author describes investigations of such proteins, particularly those concerned with clarification of structure -function relationships and molecular engineering, focusing on three classes of targets, namely human lysozyme, plant lectins composed of hevein-type domains and extracellular domains of human Fas ligand and Fas receptor. With each class of proteins, biological functions relevant to therapeutic applications, structural features, development of sample preparation methods and the experimental results for the clarification of structure -function relationships, including those of protein engineering studies on the basis of their three-dimensional structures, is summarized in the light of our current knowledge. The studies were performed by elucidating details in structural and functional consequences after introducing ligand complex formations, site-directed mutagenesis and site-specific chemical modifications, which employed various biochemical and biophysical analyses in combination with newly developed recombinant expression and chemical synthesis methods. The main findings from the studies include basic principles concerning the structure -function relationships in the enzymatic catalysis by endoglycosidases and carbohydrate recognition by lectins as well as biotechnological advances in the use of extracellular domains of death ligands and death receptors. The experimental results reviewed here will contribute to the future development of novel disulfide-bridged proteins with therapeutic usefulness targeting unmet medical needs.

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“…Granzyme B-mediated cytolysis participates in the rejection of allogeneic tumors and tissues. Mouse models deficient in granzyme B and its downstream granzymes have impaired clearance of allogeneic tumors, and the perforin-granzyme pathway contributes to graft-versus-tumor effects (51)(52)(53). However, there is also some evidence of fratricidal effects of granzyme B on other CD8 + T cells, which can impair GVT (54).…”

Section: Perforin-granzymementioning

confidence: 99%

Genetically engineered donor T cells to optimize graft‐versus‐tumor effects across MHC barriers

Ghosh

Holland

Brink

2013

Immunological Reviews

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Summary Hematopoietic stem cell transplantation has been used for more than 50 years to combat hematologic malignancies. In addition to being the first stem cell therapy, transplantation has provided evidence for the potent anti-tumor effects of T cells. Facilitating T-cell-based immunity against malignancies requires a careful balancing act between generating a robust response and avoiding off-target killing of healthy tissues, which is difficult to accomplish using bulk donor T cells. To address these issues, several approaches have been developed, drawing on basic T-cell biology, to potentiate graft-versus-tumor activity while avoiding graft-versus-host disease. Current strategies for anti-tumor cell therapies include (i) selecting optimal T cells for transfer, (ii) engineering T cells to possess enhanced effector functions, and (iii) generating T-cell precursors that complete development after adoptive transfer. In this review, we assess the current state of the art in T-lineage cell therapy to treat malignancies in the context of allogeneic hematopoietic stem cell transplantation.

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Recombinant CD95-Fc (APG101) prevents graft-versus-host disease in mice without disabling antitumor cytotoxicity and T-cell functions

Abstract: Key Points• The novel recombinant protein APG101 preventing CD95/ CD95L interaction inhibits GVHD without abrogating the GVT effect or T-cell functions.• APG101 might be incorporated into protocols of GVHD prevention and treatment during bone marrow transplantation.

Cited by 8 publications

References 52 publications

Clinical Response to the CD95-Ligand Inhibitor Asunercept Is Defined by a Pro-Inflammatory Serum Cytokine Profile

Clinical Response to the CD95-Ligand Inhibitor Asunercept Is Defined by a Pro-Inflammatory Serum Cytokine Profile

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Genetically engineered donor T cells to optimize graft‐versus‐tumor effects across MHC barriers

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