Center for Molecular Medicine Cologne

Simonis, Alexander - CAP 27

Novel immunotherapeutic approaches in the treatment of severe bacterial infections

Introduction 

Bacterial infections pose still a major threat to human health around the world, which is aggravated by the appearance and spread of antimicrobial resistances. To overcome the limited amount of new chemical substances with antibiotic activity, development of targeted therapies seems reasonable. While targeted therapeutics based on antibodies have achieved great success in cancer therapy and as shown recently, in the treatment of viral infections such as COVID-19 and HIV, the development and application of monoclonal antibodies (mAb) in treatment of bacterial infections is still in early stages of discovery.

The aim of our research group is to establish a comprehensive platform to develop monoclonal antibodies for the treatment of severe bacterial infections including infections with multidrug-resistant (MDR) isolates. This platform is composed of different screening assays to identify individuals with antibacterial antibodies among a study cohort, followed by the characterization and production of patient-derived monoclonal antibodies from specific B cells. Mode of action of these antibodies includes direct inhibition of specific bacterial virulence factors, enhancing opsonophagocytosis or activation of the complement cascade and subsequent bacteriolysis. This approach allows us to identify and to produce a multitude of diverse antibodies targeting various MDR bacteria and represents a nearly exhaustless source of new antibodies, target epitopes and therapeutic approaches. Monoclonal antibodies with proven protective effects are supposed to be further evaluated in clinical trials and will hopefully provide a basis for lifesaving new therapeutics for severe infections with MDR bacteria as well as prophylactic treatment for immunocompromised patients in the future.

Targeting bacterial virulence factors by monoclonal antibodies

As Proof-of-Concept of our approach we have focused on the development of patient-derived anti-PcrV antibodies targeting Pseudomonas aeruginosa. P. aeruginosa is a Gram-negative bacterium with high levels of intrinsic and extrinsic antibiotic resistance mechanisms and is a frequent cause of severe infections especially in critically ill and immunocompromised patients. Pathogenicity of P. aeruginosa is mediated by several virulence factors such as lipopolysaccharide, type 4 pili, and the type three secretion system (T3SS). The T3SS is located at the outer membrane of P. aeruginosa and is composed of several proteins, including the PcrV protein. As the T3SS has been linked with bacterial persistence, higher relapse rates and increased mortality in infected patients, the T3SS represents an excellent therapeutic target.
Interestingly, we were able to identify individuals with antibodies with high binding capacity and neutralizing characteristics to the PcrV protein in a large study cohort. By isolation of PcrV-specific B cells from donors with evidence of highly protective anti-PcrV antibodies, we performed in-depth analyses of the B cell receptor repertoire and were able to produce numerous monoclonal anti-PcrV antibodies with highly neutralizing qualities against P. aeruginosa. Based on the proven feasibility and effectiveness of our Proof-of-Concept study, we are planning to establish a comprehensive platform to develop monoclonal antibodies targeting several virulence factors of P. aeruginosa and other clinically relevant bacterial infections.

Enhancing innate and adaptive immune crosstalk to defend bacterial pathogens

In contrast to the described inhibition of bacterial virulence factors, antibodies can induce a strong innate immune response including the activation of the complement cascade and an enhanced phagocytosis. Based on developed screening assay we are focusing on the identification of antibodies, which are highly effective to induce an innate immune response. These screening assays will be integrated into the envisaged platform to identify, characterize, and produce antibodies, that bind bacteria and can induce an innate immune response such as an enhanced opsonophagocytosis by macrophages or an activation of the complement cascade and subsequent bacteriolysis.

Clinical relevance

This project will provide a platform for the detection and production of a multitude of diverse antibodies targeting several bacterial pathogens. For future clinical application, the combination of antibodies targeting different virulence factors simultaneously or the modification of antibodies could enhance efficacy dramatically and will be addressed in our proposed studies.  
Development of antibacterial antibodies could enable clinicians worldwide to augment their standard therapy against lifethreatening bacterial infections with a novel and potent therapy. Moreover, we are highly interested in molecular mechanisms of host-pathogen interactions and development of infection models, both key elements for revealing the pathogenesis of bacterial infections and for the development of new therapeutic approaches.

Our aims and further perspectives

The ultimate aim of our projects will be to work towards the “bench to bedside” concept to provide a basis for the authorization of potentially lifesaving new therapeutics for severe bacterial infections:

  • Gain new insights into the host-pathogen interactions of bacterial infections including in-depth analyses of the adaptive and innate immune response
  • Study the infection pathogenesis and new treatment options for various clinically relevant bacteria especially in the immunocompromised host as well as in septicemia
  • Development and advancement of infection models
  • Targeting bacteria by monoclonal antibodies including
  1. Identification of antibodies with antibacterial activity (targeting various pathogens/virulence factors)
  2. Production, characterization and modification of antibacterial antibodies
  3. In vitro and in vivo validation of the produced antibodies
  4. Monoclonal antibodies with proven protective effects in vivo are supposed to be further evaluated in clinical trials
  • Evaluation of additional immunotherapeutic approaches in the treatment of bacterial infections
  • Theobald SJ*, Simonis A*, Mudler JM*, Göbel U, Acton R, Kohlhas V, Albert MC, Hellmann AM, Malin JJ, Winter S, Hallek M, Walczak H, Nguyen PH, Koch M, Rybniker J. Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination. EMBO Mol Med. 2022 Jul 4:e15888.
  • Taromi S, Firat E, Simonis A, Braun LM, Apostolova P, Elze M, Passlick B, Schumacher A, Lagies S, Frey A, Schmitt-Graeff A, Burger M, Schmittlutz K, Follo M, von Elverfeldt D, Zhu X, Kammerer B, Diederichs S, Duyster J, Manz MG, Niedermann G, Zeiser R. Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer. Cancer Lett. 2022 Jul 10;538:215697.
  • Theobald SJ*, Simonis A*, Georgomanolis T, Kreer C, Zehner M, Eisfeld HS, Albert MC, Chhen J, Motameny S, Erger F, Fischer J, Malin JJ, Gräb J, Winter S, Pouikli A, David F, Böll B, Koehler P, Vanshylla K, Gruell H, Suárez I, Hallek M, Fätkenheuer G, Jung N, Cornely OA, Lehmann C, Tessarz P, Altmüller J, Nürnberg P, Kashkar H, Klein F, Koch M, Rybniker J. Longlived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19. EMBO Mol Med. 2021 Aug 9;13(8):e14150.
  • Simonis A*, Russkamp NF*, Mueller J, Wilk CM, Wildschut MHE, Myburgh R, Wildner-Verhey van Wijk N, Mueller R, Balabanov S, Valk PJM, Theocharides APA, Manz MG. Disruption of CSF-1R signaling inhibits growth of AML with inv(16). Blood Adv. 2021 Mar 9;5(5):1273-1277.
  • Myburgh R, Kiefer JD, Russkamp NF, Magnani CF, Nuñez N, Simonis A, Pfister S, Wilk CM, McHugh D, Friemel J, Müller AM, Becher B, Münz C, van den Broek M, Neri D, Manz MG. Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells. Leukemia. 2020 Oct;34(10):2688-2703.
  • von Ambüren J, Schreiber F, Fischer J, Winter S, van Gumpel E, Simonis A*, Rybniker J*. Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium. Microorganisms. 2020 Jul 22;8(8):1096.
  • Simonis A, Schubert-Unkmeir A. Interactions of meningococcal virulence factors with endothelial cells at the human blood-cerebrospinal fluid barrier and their role in pathogenicity. FEBS Lett. 2016 Nov;590(21):3854-3867.
  • Simonis A, Hebling S, Gulbins E, Schneider-Schaulies S, Schubert-Unkmeir A. Differential activation of acid sphingomyelinase and ceramide release determines invasiveness of Neisseria meningitidis into brain endothelial cells. PLoS Pathog. 2014 Jun 12;10(6):e1004160.

*Contributed equally

  • Theobald SJ*, Simonis A*, Mudler JM*, Göbel U, Acton R, Kohlhas V, Albert MC, Hellmann AM, Malin JJ, Winter S, Hallek M, Walczak H, Nguyen PH, Koch M, Rybniker J. Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination. EMBO Mol Med. 2022 Jul 4:e15888.
  • Taromi S, Firat E, Simonis A, Braun LM, Apostolova P, Elze M, Passlick B, Schumacher A, Lagies S, Frey A, Schmitt-Graeff A, Burger M, Schmittlutz K, Follo M, von Elverfeldt D, Zhu X, Kammerer B, Diederichs S, Duyster J, Manz MG, Niedermann G, Zeiser R. Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer. Cancer Lett. 2022 Jul 10;538:215697.
  • Simonis A, Theobald SJ, Fätkenheuer G, Rybniker J, Malin JJ. A comparative analysis of remdesivir and other repurposed antivirals against SARS-CoV-2. EMBO Mol Med. 2021 Jan 11;13(1):e13105.
  • Sörgel F, Malin JJ, Hagmann H, Kinzig M, Bilal M, Eichenauer DA, Scherf-Clavel O, Simonis A, El Tabei L, Fuhr U, Rybniker J. Pharmacokinetics of remdesivir in a COVID-19 patient with end-stage renal disease on intermittent haemodialysis. J Antimicrob Chemother. 2021 Feb 11;76(3):825-827.
  • Theobald SJ*, Simonis A*, Georgomanolis T, Kreer C, Zehner M, Eisfeld HS, Albert MC, Chhen J, Motameny S, Erger F, Fischer J, Malin JJ, Gräb J, Winter S, Pouikli A, David F, Böll B, Koehler P, Vanshylla K, Gruell H, Suárez I, Hallek M, Fätkenheuer G, Jung N, Cornely OA, Lehmann C, Tessarz P, Altmüller J, Nürnberg P, Kashkar H, Klein F, Koch M, Rybniker J. Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19. EMBO Mol Med. 2021 Aug 9;13(8):e14150.
  • Simonis A*, Russkamp NF*, Mueller J, Wilk CM, Wildschut MHE, Myburgh R, Wildner-Verhey van Wijk N, Mueller R, Balabanov S, Valk PJM, Theocharides APA, Manz MG. Disruption of CSF-1R sig-naling inhib-its growth of AML with inv(16). Blood Adv. 2021 Mar 9;5(5):1273-1277.
  • Eisfeld HS, Simonis A, Winter S, Chhen J, Ströh LJ, Krey T, Koch M, Theobald SJ, Rybniker J. Viral Glycoproteins Induce NLRP3 Inflammasome Activation and Pyroptosis in Macrophages. Viruses. 2021 Oct 15;13(10):2076.
  • von Ambüren J, Schreiber F, Fischer J, Winter S, van Gumpel E, Simonis A*, Rybniker J*. Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium. Microorganisms. 2020 Jul 22;8(8):1096.
  • Myburgh R, Kiefer JD, Russkamp NF, Magnani CF, Nuñez N, Simonis A, Pfister S, Wilk CM, McHugh D, Friemel J, Müller AM, Becher B, Münz C, van den Broek M, Neri D, Manz MG. Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells. Leukemia. 2020 Oct;34(10):2688-2703.
  • Simonis A, Schubert-Unkmeir A. The role of acid sphingomyelinase and modulation of sphingolipid metabolism in bacterial infection. Biol Chem. 2018 Sep 25;399(10):1135-1146.
  • Simonis A, Fux M, Nair G, Mueller NJ, Haralambieva E, Pabst T, Pachlopnik Schmid J, Schmidt A, Schanz U, Manz MG, Müller AMS. Allogeneic hematopoietic cell transplantation in patients with GATA2 deficiency-a case report and comprehensive review of the literature. Ann Hematol. 2018 Oct;97(10):1961-1973.
  • Simonis A, Schubert-Unkmeir A. Interactions of meningococcal virulence factors with endothelial cells at the human blood-cerebrospinal fluid barrier and their role in pathogenicity. FEBS Lett. 2016 Nov;590(21):3854-3867.
  • Simonis A, Hebling S, Gulbins E, Schneider-Schaulies S, Schubert-Unkmeir A. Differential activation of acid sphingomyelinase and ceramide release determines invasiveness of Neisseria meningitidis into brain endothelial cells. PLoS Pathog. 2014 Jun 12;10(6):e1004160.
Dr. Alexander Simonis CMMC Cologne
Dr. Alexander Simonis

Clinic I of Internal Medicine

CMMC - PI - CAP 27

+49 221 478 89608

Clinic I of Internal Medicine

Kerpener Str. 62

50937 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications - Alexander Simonis

Linkt to PubMed

Group Members

Postdoc: Dr. rer. nat. Alexandra Albus
PhD student: application process pending
TA: Dmitriy Holzmann
MD student: Kristin Schmitt