AbstractThe identification and quantification of biomarkers in clinical blood samples play a pivotal role in personalized medicine, enabling disease monitoring and therapeutic assessment. Protein phosphorylation, a key post-translational modification, reflects cellular signaling in immune or tumor cells. To exploit this, we developed a platform detecting phosphorylation states of key signaling proteins from clinical blood samples via flow cytometry. Our approach analyzes phosphorylated STAT5 (pSTAT5), ERK1/2 (pERK1/2), and p38 (p-p38), vital components in immune regulation and cancer progression.A major challenge in the analysis of phosphorylated proteins is the rapid degradation or change in phosphorylation state ex vivo, which requires immediate stabilization of samples after collection. To solve this problem, we use Smart Tubes, which enable rapid fixation of clinical blood samples and preserve the phosphorylation state upon collection, ensuring signal integrity and minimizing variability. Sample collection with Smart Tubes requires no technical equipment and can be easily implemented and standardized at any clinical trial site.Our test system employs flow cytometry, enabling the analysis of linage-specific markers (e.g., T/B cells, monocytes) and phospho-specific antibodies to quantitatively detect pSTAT5, pERK1/2, and p-p38 in peripheral blood mononuclear cell (PBMCs) subpopulations. Validation experiments with specific inhibitors demonstrate sensitivity and specificity in detecting these phosphorylated targets, even in heterogeneous cell populations within blood samples. The method allows for its application across a range of clinical conditions, from cancer immunotherapy monitoring to autoimmune disease characterization.By integrating rapid sample fixation with advanced analytical techniques, this platform addresses key challenges in analyzing phosphorylated biomarkers in clinical samples. The use of flow cytometry as the central analytical tool enables single-cell resolution, allowing detailed investigation of individual cell populations within complex samples by differential marker expression. This precision makes it possible to differentiate and study specific subpopulations of immune cells or circulating tumor cells, within a heterogeneous sample. The ability to preserve and accurately measure phosphorylation states directly in patient-derived samples provides invaluable insights into real-time cellular signaling and facilitates the optimization of therapeutic strategies targeting dysregulated signaling pathways.In summary, our system can detect phosphorylated proteins in clinical samples, with Smart Tubes ensuring sample stability and reliable biomarker analysis, advancing translational research and precision medicine.Citation Format:Valerie Oberhardt, Philipp Metzger, Carla N. Castro, Holger Weber. Detection of phosphorylated biomarkers in clinical blood samples: a flow cytometry platform utilizing smart tube fixation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4616.

2025-04-21·Cancer Research

Abstract 1314: Enhanced metastasis modeling in mice: impact of primary tumor removal and optimized injection techniques on therapeutic assessment

作者: Borrero-Wolff, Dennis ; Metzger, Philipp ; Sonntag, Roland ; Obodozie, Cynthia ; Bijelic, Gojko ; Weber, Holger ; Hummel, Jonas

AbstractThe clinical potential of therapies on tumor metastases can be specifically tested on metastases that have naturally developed through the migration of the tumor cells from the primary tumor. Removing the primary tumor allows for a clearer assessment of a substance’s efficacy in targeting metastatic sites alone, free from the influence of the primary tumor. If the primary tumor is still present during treatment, it is difficult to determine whether the reduction in metastatic spread is due to the anti-metastatic effect of the treatment or merely to the reduced growth of the primary tumor, which could indirectly limit the progression of metastases. In addition, the rapid growth of the primary tumor reduces the therapeutic window. The intra-mammary implantation approach (also referred to by us as subQperior for non-breast tumor cells) allows for clean surgical removal of the primary tumor, as the tumor remains isolated without adhering to the skin or peritoneum. This uncomplicated removal minimizes local trauma and residual primary tumor and provides a consistent basis for studying metastatic development after tumor resection.The study of metastasis in mouse models following primary tumor removal provides essential insights into the progression and treatment of metastatic disease. In this context, the luciferase-labelled 4T1 tumor cell line, known for its high metastatic potential, offers a robust model, particularly for investigating lung metastasis. After subQperior implantation of mice, we show that 4T1 cells even at small tumor sizes metastasize rapidly, predominantly to the lungs, making this model highly suitable for evaluating therapeutic strategies against metastatic spread.Furthermore, experiments with LL-2 tumor cells have shown that subQperior injection and removal of the primary tumor provides significantly better metastasis compared to traditional subcutaneous application. The approach of subQperior application not only increases the homogeneity and growth of the tumor and simplifies the removal of the primary tumor, but also comes closer to an orthotopic implantation with regard to the natural tumor environment and the progression of tumor growth. The advantages of subQperior injection suggest it may be a preferable method for achieving more consistent and representative metastasis in preclinical studies.Together, the methodological improvement of primary tumor removal and refined injection techniques enable a more precise evaluation of drugs targeting metastasis, avoiding confounding effects associated with the presence of the primary tumor. By isolating the impact of therapies on metastatic sites, researchers can more accurately assess the effectiveness of anti-metastatic agents, advancing our understanding and treatment of metastatic disease.Citation Format:Jonas Hummel, Philipp Metzger, Roland Sonntag, Dennis Borrero-Wolff, Gojko Bijelic, Cynthia Obodozie, Holger Weber. Enhanced metastasis modeling in mice: impact of primary tumor removal and optimized injection techniques on therapeutic assessment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1314.

2025-04-21·Cancer Research

Abstract 2891: In vitro comparison of Kadcyla and Enhertu in breast cancer with varying HER2 expression: proliferation, internalization, bystander effects and toxicity

作者: Metzger, Philipp ; Ehlert, Jan Eric ; Oberhardt, Valerie ; Bergo, Veronica ; Weber, Holger

AbstractHER2-positive breast cancer is characterized by overexpression of the HER2 receptor, driving aggressive tumor growth. Antibody-drug conjugates (ADCs), like trastuzumab emtansine (Kadcyla, T-DM1) and trastuzumab deruxtecan (Enhertu, T-DXd), are effective in targeting HER2-positive tumors, though their efficacy across varying HER2 levels remains under study. This study compares Kadcyla and Enhertu regarding cell proliferation, ADC internalization, and bystander cytotoxicity in cancer cell lines with high (SK-BR-3/SKOV-3), moderate (JIMT-1), and low (MDA-MB-231/MDA-MB-435) HER2 expression. It also examines off-site ADC toxicity in primary non-tumor cells caused by off-target payload delivery.The xCELLigence system, which works via label-free impedance measurements on living cells, was employed to monitor real-time cell proliferation and viability. Both, Kadcyla and Enhertu, eliminate tumor cells, effectively at nanomolar concentrations, correlating with HER2 expression levels. Interestingly, Kadcyla's effect appears at least 24 hours earlier than Enhertu, whereas the unconjugated antibody Trastuzumab itself has little to no effect on tumor cell growth. Low HER2-expressing cells were killed at 1 µM, the highest dose tested. ADC internalization was analyzed using pH-sensitive, fluorescently labeled Trastuzumab in flow cytometry and microscopy, assessing uptake by mean fluorescence intensity (MFI) in viable cells. This analysis allowed the comparison of the rate and extent of Trastuzumab uptake across the tested cell lines. A co-culture system evaluated bystander effects, with high HER2-expressing SKOV-3/SK-BR-3 cells co-cultured with luciferase-labeled HER2-negative LN-229 cells. After treatment with Kadcyla or Enhertu, luciferase assays were conducted to assess whether the cytotoxic payload released by the ADCs in HER2-positive cells could affect the viability of neighboring HER2-negative cells. Enhertu demonstrated a bystander effect, whereas Kadcyla, on the other hand, showed a more limited activity, reflecting the non-cleavable linker and the membrane-impermeable nature of its payload DM1.Toxicity analyses of Kadcyla and Enhertu on non-tumor cells, and especially on bone marrow, complement on-target investigations by revealing critical results about their safety profiles. While these ADCs are designed to selectively target tumor cells, off-site toxicity can affect healthy tissues and impair immune system function. Studies on hematopoietic stem cells are essential to assess potential adverse effects on hematopoietic regeneration and differentiation, aiming to reduce unintended immunosuppression. These findings support the optimization of ADC design, to enhance both selectivity and therapeutic windows.Citation Format:Veronica Bergo, Philipp Metzger, Valerie Oberhardt, Jan Eric Ehlert, Holger Weber. In vitro comparison of Kadcyla and Enhertu in breast cancer with varying HER2 expression: proliferation, internalization, bystander effects and toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2891.

项与 Reaction Biology Europe GmbH 相关的新闻（医药）

2020-01-28

·BioSpace

Bionetix, ProQinase, and MercachemSyncom Announce a Joint Research Project from Target Identification to Clinical Study

Bionetix, ProQinase and MercachemSyncom announced they have signed a joint multiyear integrated drug-discovery project, starting from target identification up to clinical candidate selection on an undisclosed target aimed at acute myeloid leukemia. SUWON, Korea, FREIBURG, Germany and NIJMEGEN–GRONINGEN, the Netherlands, January 27, 2020 / B3C newswire / -- Bionetix , a biotech company developing novel oncology drugs; ProQinase , an oncology-focused contract research organization (CRO) recently acquired by Reaction Biology Corporation (Malvern/PA, USA); and MercachemSyncom , a chemistry CRO specializing in medicinal chemistry and comprehensive medicinal chemistry (CMC), today announced they have signed a joint multiyear integrated drug-discovery project, starting from target identification (TI) up to clinical candidate selection on an undisclosed target aimed at acute myeloid leukemia (AML). The goal of the three-party team is to advance the project to the clinical phase by 2023. The total investment sum is “significant, of multimillion Euros”, but details are not being disclosed. “We are excited to start this new project with MercachemSyncom and ProQinase,” said Dr. DooYoung Jung, CEO of Bionetix. “They have proven their quality in another project of ours, which is currently in the early development phase. When this new opportunity came up, our decision was quick and easy. We are convinced that the team will advance this program very efficiently.” Dr. Frank Leemhuis, Managing Director of MercachemSyncom, commented: “Our skilled and experienced team has a proven track record in medicinal chemistry and CMC and built valuable research assets, as the result of a consistent innovation strategy. This research project is an opportunity to build on these qualities, with the goal of serving and creating value for our client. ProQinase is our trusted biology partner, through years of collaboration. Together with Bionetix, we look forward to making essential contributions to this oncology program.” “We are very grateful for our long-lasting partnership with MercachemSyncom, which enables us to deliver combined top-class scientific expertise to Bionetix,” said Dr. Sebastian Dempe, Chief Executive Officer of ProQinase. “This new opportunity of a multiyear collaboration, utilizing our entire breadth of oncology preclinical services, aims to develop a high-value asset for our mutual client. Working together on solid but flexible research plans, combined with efficiency, allow for short lead times and robust data-generation processes, which are key to the success of such integrated drug-discovery projects. With MercachemSyncom, we will make sure that our promises to Bionetix are met.” About Bionetix, Inc. Bionetix, Inc. (‘Bionetix’) is a development-stage biotech, focusing on the development of innovative small-molecule-based, new drugs. With the aim of providing novel solutions to patients with high unmet medical needs, Bionetix was founded in 2017 and is developing IND-ready stage candidates, along with other early-stage programs in oncology. The combination of a unique operation system and industrial expertise of the Bionetix team enables the fast development of preclinical programs and efficient identification and incubation of novel, innovative, early-stage programs. About ProQinase GmbH Based in Freiburg, Germany, ProQinase GmbH, recently acquired by Reaction Biology Corp, located in Malvern, PA, USA, is an industry leader and innovator for early-stage drug discovery. The combined company specializes in biochemical and cell-based assay services, protein production, and (immune-) oncology in vivo animal models, with over 1500 clients worldwide. Being the leading provider of kinase-based discovery services, with 660 kinases covered in the industry’s largest global offering of its kind, the global service portfolio offers an end-to-end solution, including partnering for integrated drug-discovery projects. About MercachemSyncom MercachemSyncom is the leading European CRO, offering innovative chemistry, medicinal chemistry, early process research services, and GMP production to accelerate the drug-discovery and development process in a flexible and cost-effective way. MercachemSyncom offers integrated drug-discovery services from hit to clinic. Working for many pharmaceutical and biotech companies throughout the world, MercachemSyncom is recognized for its high-quality products and services and its unprecedented problem-solving capabilities. Contacts Bionetix Inc. Dr. Hyuny Cho Chief Operating Officer +82 31-8064-1316 hyuny.cho@bionetixrx.com MercachemSyncom Dr. Frank Leemhuis Managing Director +31 24 3723300 Frank.leemhuis@mercachem.com ProQinase GmbH: Dr. Sebastian Dempe CEO/ Managing Director +49-176-80 77 61 34 s.dempe@proqinase.com

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