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  1. Article ; Online: An Fc-modified monoclonal antibody as novel treatment option for pancreatic cancer.

    Lutz, Martina S / Wang, Kevin / Jung, Gundram / Salih, Helmut R / Hagelstein, Ilona

    Frontiers in immunology

    2024  Volume 15, Page(s) 1343929

    Abstract: Pancreatic cancer is a highly lethal disease with limited treatment options. Hence, there is a considerable medical need for novel treatment strategies. Monoclonal antibodies (mAbs) have significantly improved cancer therapy, primarily due to their ... ...

    Abstract Pancreatic cancer is a highly lethal disease with limited treatment options. Hence, there is a considerable medical need for novel treatment strategies. Monoclonal antibodies (mAbs) have significantly improved cancer therapy, primarily due to their ability to stimulate antibody-dependent cellular cytotoxicity (ADCC), which plays a crucial role in their therapeutic efficacy. As a result, significant effort has been focused on improving this critical function by engineering mAbs with Fc regions that have increased affinity for the Fc receptor CD16 expressed on natural killer (NK) cells, the major cell population that mediates ADCC in humans. Here we report on the preclinical characterization of a mAb directed to the target antigen B7-H3 (CD276) containing an Fc part with the amino acid substitutions S239D/I332E to increase affinity for CD16 (B7-H3-SDIE) for the treatment of pancreatic cancer. B7-H3 (CD276) is highly expressed in many tumor entities, whereas expression on healthy tissues is more limited. Our findings confirm high expression of B7-H3 on pancreatic cancer cells. Furthermore, our study shows that B7-H3-SDIE effectively activates NK cells against pancreatic cancer cells in an antigen-dependent manner, as demonstrated by the analysis of NK cell activation, degranulation and cytokine release. The activation of NK cells resulted in significant tumor cell lysis in both short-term and long-term cytotoxicity assays. In conclusion, B7-H3-SDIE constitutes a promising agent for the treatment of pancreatic cancer.
    MeSH term(s) Humans ; Immunotherapy/methods ; Antibody-Dependent Cell Cytotoxicity ; Antibodies, Monoclonal ; Killer Cells, Natural ; Pancreatic Neoplasms/metabolism ; B7 Antigens/metabolism
    Chemical Substances Antibodies, Monoclonal ; CD276 protein, human ; B7 Antigens
    Language English
    Publishing date 2024-01-22
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2024.1343929
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  2. Article ; Online: The bispecific B7H3xCD3 antibody CC-3 induces T cell immunity against bone and soft tissue sarcomas.

    Holzmayer, Samuel J / Liebel, Kai / Hagelstein, Ilona / Salih, Helmut R / Märklin, Melanie

    Frontiers in immunology

    2024  Volume 15, Page(s) 1391954

    Abstract: Sarcomas are rare and heterogeneous malignancies that are difficult to treat. Approximately 50% of patients diagnosed with sarcoma develop metastatic disease with so far very limited treatment options. The transmembrane protein B7-H3 reportedly is ... ...

    Abstract Sarcomas are rare and heterogeneous malignancies that are difficult to treat. Approximately 50% of patients diagnosed with sarcoma develop metastatic disease with so far very limited treatment options. The transmembrane protein B7-H3 reportedly is expressed in various malignancies, including different sarcoma subtypes. In several cancer entities B7-H3 expression is associated with poor prognosis. In turn, B7-H3 is considered a promising target for immunotherapeutic approaches. We here report on the preclinical characterization of a B7-H3xCD3 bispecific antibody in an IgG-based format, termed CC-3, for treatment of different sarcoma subtypes. We found B7-H3 to be expressed on all sarcoma cells tested and expression on sarcoma patients correlated with decreased progression-free and overall survival. CC-3 was found to elicit robust T cell responses against multiple sarcoma subtypes, resulting in significant activation, release of cytokines and effector molecules. In addition, CC-3 promoted T cell proliferation and differentiation, resulting in the generation of memory T cell subsets. Finally, CC-3 induced potent target cell lysis in a target cell restricted manner. Based on these results, a clinical trial evaluating CC-3 in soft tissue sarcoma is currently in preparation.
    MeSH term(s) Humans ; Antibodies, Bispecific/pharmacology ; Antibodies, Bispecific/therapeutic use ; Sarcoma/immunology ; Sarcoma/drug therapy ; B7 Antigens/immunology ; B7 Antigens/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Cell Line, Tumor ; Bone Neoplasms/immunology ; Bone Neoplasms/pathology ; Female ; Male ; Animals ; Lymphocyte Activation/immunology ; Middle Aged ; CD3 Complex/immunology ; Aged ; Cell Proliferation ; Adult
    Chemical Substances CD276 protein, human
    Language English
    Publishing date 2024-05-03
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2024.1391954
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  3. Book ; Online ; Thesis: Anti-Tumor Antikörper mit verbesserter Rekrutierung von Weichteil- und Knochensarkomen

    Hagelstein, Ilona [Verfasser] / Salih, Helmut R. [Akademischer Betreuer]

    2023  

    Author's details Ilona Hagelstein ; Betreuer: Helmut R. Salih
    Keywords Naturwissenschaften ; Science
    Subject code sg500
    Language German
    Publisher Universitätsbibliothek Tübingen
    Publishing place Tübingen
    Document type Book ; Online ; Thesis
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  4. Book ; Online ; Thesis: Ein Fc-optimierter CD133 Antikörper zur Induktion einer Immunantwort natürlicher Killerzellen gegen das kolorektale Karzinom und die akute lymphatische Leukämie

    Riegg, Fabian [Verfasser] / Salih, Helmut R. [Akademischer Betreuer]

    2023  

    Author's details Fabian Alexander Riegg ; Betreuer: Helmut R. Salih
    Keywords Medizin, Gesundheit ; Medicine, Health
    Subject code sg610
    Language German
    Publisher Universitätsbibliothek Tübingen
    Publishing place Tübingen
    Document type Book ; Online ; Thesis
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  5. Article ; Online: The challenges of translation.

    Salih, Helmut R / Jung, Gundram

    EMBO molecular medicine

    2019  Volume 11, Issue 12, Page(s) e10874

    Abstract: Cancer immunotherapy is a highly active area in translational medicine where the challenges and rewards of developing new drugs "from bench to bedside" become particularly visible. Here, we comment on both, the scientific and non-scientific hurdles of ... ...

    Abstract Cancer immunotherapy is a highly active area in translational medicine where the challenges and rewards of developing new drugs "from bench to bedside" become particularly visible. Here, we comment on both, the scientific and non-scientific hurdles of this translational process using the example of bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells, two closely related strategies for antibody-guided recruitment of T cells against cancer. Both exert impressive therapeutic activity and were recently approved for treatment of B-cell malignancies. We discuss how the efficacy of these auspicious therapeutic tools may be further improved, in particular against solid tumors, but we also address another critical issue: Since both approaches were already introduced in the 1980s, why did it take almost thirty years until they became clinically available?
    MeSH term(s) Antibodies, Bispecific/immunology ; Humans ; Immunotherapy/methods ; Immunotherapy, Adoptive/methods ; Neoplasms/immunology ; Neoplasms/therapy ; Receptors, Antigen, T-Cell/metabolism ; Tumor Microenvironment/immunology
    Chemical Substances Antibodies, Bispecific ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2019-10-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.201910874
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6784: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  6. Article: Bispecific Antibodies in Prostate Cancer Therapy: Current Status and Perspectives.

    Heitmann, Jonas S / Pfluegler, Martin / Jung, Gundram / Salih, Helmut R

    Cancers

    2021  Volume 13, Issue 3

    Abstract: Prostate carcinoma (PC) is the second most common cancer in men. When the disease becomes unresponsive to androgen deprivation therapy, the remaining treatment options are of limited benefit. Despite intense efforts, none of the T cell-based ... ...

    Abstract Prostate carcinoma (PC) is the second most common cancer in men. When the disease becomes unresponsive to androgen deprivation therapy, the remaining treatment options are of limited benefit. Despite intense efforts, none of the T cell-based immunotherapeutic strategies that meanwhile have become a cornerstone for treatment of other malignancies is established in PC. This refers to immune checkpoint inhibition (CI), which generally reinforces T cell immunity as well as chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) that stimulate the T cell receptor/CD3-complex and mobilize T cells in a targeted manner. In general, compared to CAR-T cells, bsAb would have the advantage of being an "off the shelf" reagent associated with less preparative effort, but at present, despite enormous efforts, neither CAR-T cells nor bsAbs are successful in solid tumors. Here, we focus on the various bispecific constructs that are presently in development for treatment of PC, and discuss underlying concepts and the state of clinical evaluation as well as future perspectives.
    Language English
    Publishing date 2021-02-01
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13030549
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  7. Book ; Thesis: Einfluß von Heparin auf humane Granulocyten und Monocyten

    Salih, Helmut R.

    Anwendung durchflußzytometrischer Verfahren

    1997  

    Author's details vorgelegt von Helmut Rainer Salih
    Language German
    Size 143 S. : graph. Darst.
    Document type Book ; Thesis
    Thesis / German Habilitation thesis München, Univ., Diss., 1997
    HBZ-ID HT008819183
    Database Catalogue ZB MED Medicine, Health

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    In stock of ZB MED Cologne/Königswinter

    Shelf markLoan statusLocation
    98 D 2076 order for loan Magazin

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  8. Article ; Online: Expression of the immune checkpoint modulator OX40 indicates poor survival in acute myeloid leukemia.

    Marconato, Maddalena / Kauer, Joseph / Salih, Helmut R / Märklin, Melanie / Heitmann, Jonas S

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 15856

    Abstract: Despite therapeutic advances, mortality of Acute Myeloid Leukemia (AML) is still high. Currently, the determination of prognosis which guides treatment decisions mainly relies on genetic markers. Besides molecular mechanisms, the ability of malignant ... ...

    Abstract Despite therapeutic advances, mortality of Acute Myeloid Leukemia (AML) is still high. Currently, the determination of prognosis which guides treatment decisions mainly relies on genetic markers. Besides molecular mechanisms, the ability of malignant cells to evade immune surveillance influences the disease outcome and, among others, the expression of checkpoints modulators contributes to this. In AML, functional expression of the checkpoint molecule OX40 was reported, but the prognostic relevance of OX40 and its ligand OX40L axis has so far not been investigated. Here we described expression and prognostic relevance of the checkpoint modulators OX40 and OX40L, analyzed on primary AML cells obtained from 92 therapy naïve patients. Substantial expression of OX40 and OX40L on AML blasts was detected in 29% and 32% of the investigated subjects, respectively, without correlation between the expression of the receptor and its ligand. Whereas OX40L expression was not associated with different survival, patients with high expression levels of the receptor (OX40<sup>high</sup>) on AML blasts survived significantly shorter than OX40<sup>low</sup> patients (p = 0.009, HR 0.46, 95% CI 0.24-0.86), which identifies OX40 as novel prognostic marker and a potential therapeutic target in AML patients.
    MeSH term(s) Genetic Markers ; Humans ; Immunologic Factors ; Immunologic Surveillance ; Leukemia, Myeloid, Acute/genetics ; Ligands ; OX40 Ligand/metabolism ; Receptors, OX40/metabolism ; Survival Rate
    Chemical Substances Genetic Markers ; Immunologic Factors ; Ligands ; OX40 Ligand ; Receptors, OX40 ; TNFRSF4 protein, human
    Language English
    Publishing date 2022-09-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-19972-1
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  9. Article ; Online: Novel ACE2 fusion protein with adapting activity against SARS-CoV-2 variants

    Zekri, Latifa / Ruetalo, Natalia / Christie, Mary / Walker, Carolin / Manz, Timo / Rammensee, Hans-Georg / Salih, Helmut R / Schindler, Michael / Jung, Gundram

    Frontiers in immunology

    2023  Volume 14, Page(s) 1112505

    Abstract: Despite the successful development of vaccines and neutralizing antibodies to limit the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerging variants prolong the pandemic and emphasize the persistent need to develop effective ... ...

    Abstract Despite the successful development of vaccines and neutralizing antibodies to limit the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerging variants prolong the pandemic and emphasize the persistent need to develop effective antiviral treatment regimens. Recombinant antibodies directed to the original SARS-CoV-2 have been successfully used to treat established viral disease. However, emerging viral variants escape the recognition by those antibodies. Here we report the engineering of an optimized ACE2 fusion protein, designated ACE2-M, which comprises a human IgG1 Fc domain with abrogated Fc-receptor binding linked to a catalytically-inactive ACE2 extracellular domain that displays increased apparent affinity to the B.1 spike protein. The affinity and neutralization capacity of ACE2-M is unaffected or even enhanced by mutations present in the spike protein of viral variants. In contrast, a recombinant neutralizing reference antibody, as well as antibodies present in the sera of vaccinated individuals, lose activity against such variants. With its potential to resist viral immune escape ACE2-M appears to be particularly valuable in the context of pandemic preparedness towards newly emerging coronaviruses.
    MeSH term(s) Humans ; Angiotensin-Converting Enzyme 2/genetics ; Antibodies, Neutralizing ; COVID-19 ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics ; Protein Engineering ; Recombinant Fusion Proteins
    Chemical Substances Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Recombinant Fusion Proteins
    Language English
    Publishing date 2023-03-08
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1112505
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  10. Article ; Online: IgG-based B7-H3xCD3 bispecific antibody for treatment of pancreatic, hepatic and gastric cancer.

    Lutz, Martina S / Zekri, Latifa / Weßling, Laura / Berchtold, Susanne / Heitmann, Jonas S / Lauer, Ulrich M / Jung, Gundram / Salih, Helmut R

    Frontiers in immunology

    2023  Volume 14, Page(s) 1163136

    Abstract: T cell-based immunotherapy has significantly improved treatment options for many malignancies. However, despite these and other therapeutic improvements over the last decades, gastrointestinal cancers, in particular pancreatic, hepatic and gastric cancer, ...

    Abstract T cell-based immunotherapy has significantly improved treatment options for many malignancies. However, despite these and other therapeutic improvements over the last decades, gastrointestinal cancers, in particular pancreatic, hepatic and gastric cancer, are still characterized by high relapse rates and dismal prognosis, with an accordingly high unmet medical need for novel treatment strategies. We here report on the preclinical characterization of a novel bispecific antibody in an IgG-based format termed CC-3 with B7-H3xCD3 specificity. In many cancer entities including pancreatic, hepatic and gastric cancers, B7-H3 (CD276) is overexpressed on tumor cells and also on the tumor vasculature, the latter allowing for improved access of immune effector cells into the tumor site upon therapeutic targeting. We demonstrate that CC-3 induces profound T cell reactivity against various pancreatic, hepatic and gastric cancer cell lines as revealed by analysis of activation, degranulation and secretion of IL2, IFNγ as well as perforin, resulting in potent target cell lysis. Moreover, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. Together, our results emphasize the potential of CC-3, which is presently being GMP-produced to enable clinical evaluation for treatment of pancreatic, hepatic and gastric cancer.
    MeSH term(s) Humans ; Stomach Neoplasms/therapy ; Immunoglobulin G ; Neoplasm Recurrence, Local ; T-Lymphocytes ; Immunotherapy/methods ; B7 Antigens/metabolism
    Chemical Substances Immunoglobulin G ; CD276 protein, human ; B7 Antigens
    Language English
    Publishing date 2023-04-14
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1163136
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