TRION Research GmbH

Schönau am Königssee, Germany

TRION Research GmbH

Schönau am Königssee, Germany
Time filter
Source Type

Deppisch N.,Helmholtz Center Munich | Ruf P.,Trion Research GmbH | Eissler N.,Helmholtz Center Munich | Lindhofer H.,Trion Research GmbH | Mocikat R.,Helmholtz Center Munich
Oncotarget | Year: 2017

Combinatorial approaches of immunotherapy hold great promise for the treatment of malignant disease. Here, we examined the potential of combining an immune checkpoint inhibitor and trifunctional bispecific antibodies (trAbs) in a preclinical melanoma mouse model using surrogate antibodies of Ipilimumab and Catumaxomab, both of which have already been approved for clinical use. The specific binding arms of trAbs redirect T cells to tumor cells and trigger direct cytotoxicity, while the Fc region activates accessory cells eventually giving rise to a long-lasting immunologic memory. We show here that T cells redirected to tumor cells by trAbs strongly upregulate CTLA-4 expression in vitro and in vivo. This suggested that blocking of CTLA-4 in combination with trAb treatment enhances T-cell activation in a tumor-selective manner. However, when mice were challenged with melanoma cells and subsequently treated with antibodies, there was only a moderate beneficial effect of the combinatorial approach in vivo with regard to direct tumor destruction in comparison to trAb therapy alone. By contrast, a significantly improved vaccination effect was obtained by CTLA-4 blocking during trAb-dependent immunization. This resulted in enhanced rejection of melanoma cells given after pre-immunization. The improved immunologic memory induced by the combinatorial approach correlated with an increased humoral antitumor response as measured in the sera and an expansion of CD4+ memory T cells found in the spleens.

Agency: European Commission | Branch: FP7 | Program: CP-FP-SICA | Phase: HEALTH-2009-4.3.1-1 | Award Amount: 5.16M | Year: 2010

The aim of this project is to develop a new generation vaccine for schistosomiasis. The vaccine will be based on exposed proteins and/or glycans of the vulnerable skin stage schistosomula, making it safe and effective. The life stage-specific vaccine target selection strategy is based on state-of-the-art schistosomal transcriptomics and glycomics technologies and data, and unique serum and sample libraries from endemic areas will be the key to identifying protective immune responses and effective targets. Preclinical in vitro (cellular and whole parasite) and in vivo (rat model) testing of protective antigens with respect to cellular responses and effective parasite killing are part of the development pipeline. Analysis of human T- and B-cell responsiveness is an integral part of the approach. A unique SME-led approach to potentiate the effect of immunisation by use of engineering engineered antibodies will also be part of the project. The project involves strong participation of researchers from four schistosomiasis-endemic countries, and several European groups all with a long history of successful collaboration.

PubMed | TRION Research GmbH, Goethe University Frankfurt, UCT, Onkologische Schwerpunktpraxis and University of Heidelberg
Type: | Journal: BMC cancer | Year: 2016

Ertumaxomab (ertu) is a bispecific, trifunctional antibody targeting Her2/neu, CD3 and the Fc-receptors I, IIa, and III forming a tri-cell complex between tumor cell, T cell and accessory cells.Patients (pts) with Her2/neu (1+/SISH positive, 2+ and 3+) expressing tumors progressing after standard therapy were treated to investigate safety, tolerability and preliminary efficacy. In this study, ertu was applied i.v. in 2cycles following a predefined dose escalating scheme. Each cycle consisted of five ascending doses (10-500g) applied weekly within 28days with a 21day treatment-free interval. If 2 pts experienced a dose limiting toxicity (DLT) at a given dose level, the maximum tolerated dose (MTD) had been exceeded.Fourteen heavily pretreated pts (e.g. breast, rectal, gastric cancer) were enrolled in the four main cohorts. Three (21%) pts had to be replaced. Two serious adverse events (SAE) with possible relation to the investigational drug were seen, both fully reversible. A DLT was not detected. Consequently, the MTD could not be determined. All adverse events (AE) were transient and completely reversible. Most frequent AEs were fatigue (14/14), pain (13/14), cephalgia (12/14), chills (11/14), nausea (8/14), fever (7/14), emesis (7/14) and diarrhea (5/14). Single doses up to 300g were well tolerated (total dose up to 800g per cycle). We observed one partial remission and two disease stabilizations after first treatment cycle.Single doses up to 300g could be safely administered in an escalating dose scheme. Immunological responses and clinical activity warrant further evaluation in patients with Her2 over expressing tumors.EudraCT number: 2011-003201-14; identifier: NCT01569412.

Jager M.,TRION Research GmbH | Schoberth A.,TRION Research GmbH | Ruf P.,TRION Research GmbH | Hess J.,TU Munich | And 9 more authors.
Cancer Research | Year: 2012

Patients with malignant ascites secondary to primary carcinomas benefit from intraperitoneal therapy with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3). Here, we report the analysis of peritoneal fluid samples from 258 patients with malignant ascites randomized to catumaxomab or control groups to investigate the molecular effects of catumaxomab treatment. In the catumaxomab group, tumor cell numbers and peritoneal levels of VEGF decreased, whereas the activation status of CD4 + and CD8 + T-cell populations increased more than two-fold after treatment. Notably, CD133 +/EpCAM + cancer stem cells vanished from the catumaxomab samples but not from the control samples. In vitro investigations indicated that catumaxomab eliminated tumor cells in a manner associated with release of proinflammatory Th1 cytokines. Together, our findings show that catumaxomab therapy activates peritoneal T cells and eliminates EpCAM + tumor cells, establishing a molecular and cellular basis to understand in vivo efficacy within the immunosuppressed malignant ascites tissue microenvironment. ©2011 AACR.

Pietzner K.,University Medicine of Berlin | Jager M.,TRION Research GmbH | Schoberth A.,TRION Research GmbH | Oskay-Ozcelik G.,University Medicine of Berlin | And 4 more authors.
Medical Oncology | Year: 2012

In the past, treatment for malignant ascites focussed on symptomatic relief or treatment of the underlying disease. A promising option evolved with catumaxomab (Removab®) in 2009. Since catumaxomab is a bispecific, trifunctional antibody with mouse-rat origin, so far repeated treatment cycles were not an option due to the occurrence of human anti-drug antibodies (HADA). Nevertheless, the good results obtained so far raised the question whether a repeated treatment cycle with catumaxomab could be feasible and effective. We report on a 74-year-old female patient with breast cancer and peritoneal carcinomatosis. To our knowledge, this is the first patient worldwide to be treated with a repeated cycle of catumaxomab. HAMA (human anti-mouse antibodies) values were identified in blood and ascites samples. Ascites samples were also stained to identify and quantify cells, positive for EpCAM (epithelial cell adhesion molecule) and CD45. The patient tolerated the second cycle without unexpected side effects and remained puncture-free for another 45 days. Analysis of blood and ascites revealed a quick increase in HAMA values in the blood samples after 1 week, but considerably lower HAMA values and delayed increase in the ascites samples. Also a distinct and continuous decrease of EpCAM-positive cells was observed in the ascites samples under treatment. A strong increase in CD45-positive cells was detected after the beginning of the second cycle, with a consecutive decline toward the end. This first experience suggests that a repeated cycle of catumaxomab might be feasible and effective. As a consequence, a phase II trial (SECIMAS) was initiated. © Springer Science+Business Media, LLC 2011.

Eissler N.,Helmholtz Center Munich | Ruf P.,Trion Research GmbH | Mysliwietz J.,Helmholtz Center Munich | Lindhofer H.,Trion Research GmbH | And 2 more authors.
Cancer Research | Year: 2012

A major goal of tumor immunotherapy is the induction of long-lasting systemic T-cell immunity. Bispecific antibodies (bsAbs) that lack the immunoglobulin Fc region confer T-cell-mediated killing of tumor cells but do not induce long-term memory. In contrast, trifunctional bsAbs comprise an appropriate Fc region and, therefore, not only recruit T cells but also accessory cells that bear activating Fcγ receptors (FcγR), providing additional T-cell-activating signals and securing presentation of tumor-derived antigens to T cells. In this study, we show that trifunctional bsAbs induce a polyvalent T-cell response and, therefore, a vaccination effect. Mice were treated with melanoma cells and with a trifunctional bsAb directed against the melanoma target antigen ganglioside GD2 in addition to murine CD3. The trifunctional bsAb activated dendritic cells and induced a systemic immune response that was not replicated by treatment with the F(ab′) 2-counterpart lacking the Fc region. Restimulation of spleen and lymph node cells in vitro yielded T-cell lines that specifically produced interferon-γ in response to tumor. In addition, trifunctional bsAb-induced T cells recognized various specific peptides derived from melanoma-associated antigens. Moreover, these polyvalent responses proved to be tumor-suppressive and could not be induced by the corresponding bsF(ab′)2- fragment. Taken together, our findings provide preclinical proof of concept that trifunctional bsAbs can induce tumor-specific T cells with defined antigen specificity. ©2012 AACR.

Hess J.,TRION Pharma GmbH | Ruf P.,TRION Research GmbH | Lindhofer H.,TRION Pharma GmbH | Lindhofer H.,TRION Research GmbH
Future Oncology | Year: 2012

Trifunctional antibodies (trAbs) are promising novel anticancer biologics with a particular mode of action capable of linking innate with adaptive immunity. Based on their unique structure, trifunctional IgG-like heterodimeric antibodies, consisting of nonhuman mouse and rat immunoglobulin halves are able to redirect T lymphocytes, as well as accessory cells, to the tumor site. This recruitment of immune cells is accompanied by cellular activation events elicited by anti-CD3, as well as Fcγ-receptor engagement of trAbs supported by a proinflammatory Th1-biased cytokine milieu. All necessary immunological factors required for long-term vaccination-like effects are stimulated along trAb-mediated therapeutic interventions. Thus, the concerted interplay of antibody-dependent cellular cytotoxicity plus the polyclonal T-cell cytotoxicity and Fcγ-receptor-driven induction of long-lasting immune responses after the initial tumor cell elimination represent the major hallmarks of trAb-mediated treatment of malignant diseases. © 2012 Future Medicine Ltd.

The present invention refers to a pharmaceutical composition containing trifunctional bispecific and/or trispecific antibodies being capable of binding to a specific target antigen(s) for use in a method of immunizing mammals against diseases in which said target antigen(s) is (are) involved, and further to a pharmaceutical composition containing trifunctional bispecific and/or trispecific antibodies being capable of binding to (a) specific target antigen (s) which is (are) involved in a disease of a mammal, specifically a human.

The present invention refers to a pharmaceutical composition containing trifunctional bispecific and/or trispecific antibodies being capable of binding to a specific target antigen(s) for use in a method of immunizing mammals against diseases in which said target antigen(s) is (are) involved, and further to a pharmaceutical composition containing trifunctional bispecific and/or trispecific antibodies being capable of binding to (a) specific target antigen (s) which is (are) involved in a disease of a mammal, specifically a human.

PubMed | TRION Research GmbH
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

2575 Background: Catumaxomab is the first EU approved bispecific (anti-EpCAM x anti-CD3) trifunctional antibody for the intraperitoneal (ip) treatment of malignant ascites (MA) in patients (pts) with EpCAM-positive tumors.In the ongoing phase IIIb study CASIMAS catumaxomab is investigated with/without prednisolone premedication in pts with MA due to epithelial cancer. Pts received four 3-hour infusions of 10, 20, 50 and 150 g catumaxomab over 11 days. Plasma samples of 15 pts were quantified for autologous anti-EpCAM and anti-HER2 immunoglobulin (Ig) responses by ELISA. Additionally, MA samples were screened for EpCAM-positive tumor cells by immunocytochemistry and anti-drug antibody (ADA) responses were monitored.At screening EpCAM-positive tumor cells were detected in the ascites fluid of all 15 pts. Thereof, 8 individuals (53%) showed a median 3-4 times increase of the initial anti-EpCAM Ig titer after treatment, whereas in 7/15 pts (47%) the titer did not increase. Although anti-EpCAM Ig screening values varied largely (2 -855 ng/ml) no significant distinction between the anti-EpCAM responder group (R) and non-responders (NR) was measured (p = 0.96; Mann Whitney test). However, there was a significant difference in the mean ADA concentrations of available samples determined 7 or 8 d after the last catumaxomab infusion (27,103 [R, n=5] vs. 910 ng/ml [NR, n=5]). Moreover, in 5/11evaluable pts (45%) HER2 -specific Ig could be quantified. In contrast to the augmented anti-EpCAM antibody levels which rapidly appeared (d 10) anti-HER2 responses developed de novo, started delayed (d 18) and peaked at the last sample collection (d 38, median=17 ng/ml). Interestingly, available samples of 2 pts who received a second treatment cycle after recurring MA displayed an anti-HER2 Ig booster reaction with peak levels of 48 and 209 ng/ml.The results indicate an active immunization induced by catumaxomab. Most importantly, the humoral immune response was not restricted to the EpCAM targeted but antigen spreading to the non-targeted HER2 tumor-associated antigen occurred. The impact of this immunization effect for the therapeutic benefit will be further investigated.

Loading TRION Research GmbH collaborators
Loading TRION Research GmbH collaborators