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  1. Article ; Online: Complement-targeted therapeutics: An emerging field enabled by academic drug discovery.

    Lamers, Christina / Ricklin, Daniel / Lambris, John D

    American journal of hematology

    2023  Volume 98 Suppl 4, Page(s) S82–S89

    Abstract: Within a short few years, the number of complement inhibitors that are either approved for therapeutic application or evaluated in late-stage clinical trials has expanded remarkably. The sudden emergence of this target area in the pipelines of many ... ...

    Abstract Within a short few years, the number of complement inhibitors that are either approved for therapeutic application or evaluated in late-stage clinical trials has expanded remarkably. The sudden emergence of this target area in the pipelines of many biotech start-ups and even large pharmaceutical companies appears even more surprising when considering that the involvement of the complement system in various clinical conditions had long been recognized. In many aspects, however, the complement system is far from being a traditional drug target, which may explain the delayed breakthrough of this therapeutic strategy. While complement modulation is now considered an attractive "platform technology" with applications in a wide spectrum of disorders, the broad yet heterogeneous disease involvement of the complement system has long restricted its placement in traditional drug discovery programs. Concerns about the safety of complement-targeted interventions, the large number and high plasma concentrations of target proteins, and the complexity of the complement system's engagement in biological processes are among other factors that kept complement off the drug discovery radar for decades. Alongside technical advances and financial incentives, the innovation and persistence of academic and clinical researchers have been the critical driving force to navigate complement therapeutics out of the shadow into the spotlight. In this commentary, we document this remarkable development using select examples and aim to venture some predictions where this promising field may be headed to.
    MeSH term(s) Humans ; Complement Activation ; Complement System Proteins ; Drug Discovery ; Complement Inactivating Agents/pharmacology ; Complement Inactivating Agents/therapeutic use
    Chemical Substances Complement System Proteins (9007-36-7) ; Complement Inactivating Agents
    Language English
    Publishing date 2023-02-08
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 196767-8
    ISSN 1096-8652 ; 0361-8609
    ISSN (online) 1096-8652
    ISSN 0361-8609
    DOI 10.1002/ajh.26875
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Complement & disease: out of the shadow into the spotlight.

    Ricklin, Daniel / Pouw, Richard B

    Seminars in immunopathology

    2021  Volume 43, Issue 6, Page(s) 755–756

    MeSH term(s) Complement System Proteins ; Humans
    Chemical Substances Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2021-11-15
    Publishing country Germany
    Document type Editorial
    ZDB-ID 2316828-6
    ISSN 1863-2300 ; 1863-2297
    ISSN (online) 1863-2300
    ISSN 1863-2297
    DOI 10.1007/s00281-021-00897-2
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  3. Article ; Online: Tipping the balance: intricate roles of the complement system in disease and therapy.

    Pouw, Richard B / Ricklin, Daniel

    Seminars in immunopathology

    2021  Volume 43, Issue 6, Page(s) 757–771

    Abstract: The ability of the complement system to rapidly and broadly react to microbial intruders, apoptotic cells and other threats by inducing forceful elimination responses is indispensable for its role as host defense and surveillance system. However, the ... ...

    Abstract The ability of the complement system to rapidly and broadly react to microbial intruders, apoptotic cells and other threats by inducing forceful elimination responses is indispensable for its role as host defense and surveillance system. However, the danger sensing versatility of complement may come at a steep price for patients suffering from various immune, inflammatory, age-related, or biomaterial-induced conditions. Misguided recognition of cell debris or transplants, excessive activation by microbial or damaged host cells, autoimmune events, and dysregulation of the complement response may all induce effector functions that damage rather than protect host tissue. Although complement has long been associated with disease, the prevalence, impact and complexity of complement's involvement in pathological processes is only now becoming fully recognized. While complement rarely constitutes the sole driver of disease, it acts as initiator, contributor, and/or exacerbator in numerous disorders. Identifying the factors that tip complement's balance from protective to damaging effects in a particular disease continues to prove challenging. Fortunately, however, molecular insight into complement functions, improved disease models, and growing clinical experience has led to a greatly improved understanding of complement's pathological side. The identification of novel complement-mediated indications and the clinical availability of the first therapeutic complement inhibitors has also sparked a renewed interest in developing complement-targeted drugs, which meanwhile led to new approvals and promising candidates in late-stage evaluation. More than a century after its description, complement now has truly reached the clinic and the recent developments hold great promise for diagnosis and therapy alike.
    MeSH term(s) Complement Activation ; Complement System Proteins ; Humans
    Chemical Substances Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2021-10-26
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2316828-6
    ISSN 1863-2300 ; 1863-2297
    ISSN (online) 1863-2300
    ISSN 1863-2297
    DOI 10.1007/s00281-021-00892-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Book ; Conference proceedings: Complement therapeutics

    Lambris, John D. / Holers, V. Michael / Ricklin, Daniel

    [Fifth International Complement Therapeutics Conference (June 22 - 27, 2011) in Rhodes, Greece]

    (Advances in experimental medicine and biology ; 735)

    2013  

    Event/congress International Complements Therapeutics Conference (5, 2011, Rhodos)
    Author's details John D. Lambris ; V. Michael Holers ; Daniel Ricklin ed
    Series title Advances in experimental medicine and biology ; 735
    Collection
    Keywords Complement (Immunology)
    Language English
    Size VIII, 320 S. : Ill., graph. Darst.
    Publisher Springer
    Publishing place New York u.a.
    Publishing country United States
    Document type Book ; Conference proceedings
    HBZ-ID HT017420044
    ISBN 978-1-4614-4117-5 ; 1-4614-4117-X ; 9781461441182 ; 1461441188
    Database Catalogue ZB MED Medicine, Health

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    Shelf markLoan statusLocation
    Zs A 3192 -735- not available for loan Zeitschriften-Lesesaal

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  5. Article ; Online: The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology.

    Lamers, Christina / Plüss, Carla Johanna / Ricklin, Daniel

    Frontiers in immunology

    2021  Volume 12, Page(s) 662164

    Abstract: ... The ... ...

    Abstract The β
    MeSH term(s) Animals ; Cell Movement ; Drug Development ; Humans ; Integrins/immunology ; Leukocytes/metabolism ; Ligands ; Mice ; Neutrophils/immunology ; Receptors, Complement/classification ; Receptors, Complement/immunology ; Receptors, Complement/metabolism
    Chemical Substances Integrins ; Ligands ; Receptors, Complement
    Language English
    Publishing date 2021-04-29
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.662164
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Compstatins: the dawn of clinical C3-targeted complement inhibition.

    Lamers, Christina / Mastellos, Dimitrios C / Ricklin, Daniel / Lambris, John D

    Trends in pharmacological sciences

    2022  Volume 43, Issue 8, Page(s) 629–640

    Abstract: Despite the growing recognition of the complement system as a major contributor to a variety of clinical conditions, the therapeutic arsenal has remained scarce. The introduction of an anti-C5 antibody in 2007 raised confidence in complement-targeted ... ...

    Abstract Despite the growing recognition of the complement system as a major contributor to a variety of clinical conditions, the therapeutic arsenal has remained scarce. The introduction of an anti-C5 antibody in 2007 raised confidence in complement-targeted therapy. However, it became apparent that inhibition of late-stage effector generation might not be sufficient in multifactorial complement disorders. Upstream intervention at the level of C3 activation has therefore been considered promising. The approval of pegcetacoplan, a C3 inhibitor of the compstatin family, in 2021 served as critical validation of C3-targeted treatment. This review delineates the evolution of the compstatin family from its academic origins to the clinic and highlights current and potential future applications of this promising drug class in complement diseases.
    MeSH term(s) Antibodies, Monoclonal, Humanized/pharmacology ; Complement C3/therapeutic use ; Complement System Proteins ; Hemoglobinuria, Paroxysmal/drug therapy ; Hemolysis ; Humans ; Peptides, Cyclic
    Chemical Substances Antibodies, Monoclonal, Humanized ; Complement C3 ; Peptides, Cyclic ; compstatin ; Complement System Proteins (9007-36-7) ; pegcetacoplan (TO3JYR3BOU)
    Language English
    Publishing date 2022-01-25
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 282846-7
    ISSN 1873-3735 ; 0165-6147
    ISSN (online) 1873-3735
    ISSN 0165-6147
    DOI 10.1016/j.tips.2022.01.004
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  7. Article ; Online: Exploring the function of factor XIII free B subunit: Interactions with complement factors and a novel approach to identify potential binding partners.

    Li, Bojun / Bechtler, Clément / Jenny, Lorenz / Ricklin, Daniel / Schroeder, Verena

    Research and practice in thrombosis and haemostasis

    2022  Volume 6, Issue 5, Page(s) e12766

    Abstract: Background: The factor XIII (FXIII)-B subunit has a critical function as a carrier protein to stabilize FXIII-A in plasma and supply it to its main substrate, fibrinogen. However, the function of the excess free FXIII-B circulating in plasma is still ... ...

    Abstract Background: The factor XIII (FXIII)-B subunit has a critical function as a carrier protein to stabilize FXIII-A in plasma and supply it to its main substrate, fibrinogen. However, the function of the excess free FXIII-B circulating in plasma is still elusive.
    Objectives: In the present study, we explored potential interactions of free FXIII-B with complement factors and searched for novel binding partners.
    Methods: We tested for cofactor activity in the degradation of complement C3b and C4b and used ELISA- and surface plasmon resonance-based binding assays to investigate interactions between FXIII-B and complement components. We performed immunoprecipitation and mass spectrometry analysis to identify potential binding partners of free FXIII-B in freshly drawn plasma samples.
    Results: FXIII-B did not exhibit cofactor activity in the degradation of C3b and C4b similar to factor H and C4b-binding protein, nor did it bind to complement factors to a relevant extent. Identification of proteins potentially binding to free FXIII-B revealed high interindividual variation. We confirmed α
    Conclusions: Our study reveals that free FXIII-B has no direct role in regulating the complement system, despite a structural similarity to major complement regulators. Further studies are needed to validate α2MG as a binding partner and explore potential functional consequences of this binding.
    Language English
    Publishing date 2022-07-21
    Publishing country United States
    Document type Journal Article
    ISSN 2475-0379
    ISSN (online) 2475-0379
    DOI 10.1002/rth2.12766
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Therapeutic Peptides as Emerging Options to Restore Misguided Host Defence and Homeostasis: From Teaching to Concept to Clinic.

    Schwardt, Oliver / Lamers, Christina / Bechtler, Clément / Ricklin, Daniel

    Chimia

    2021  Volume 75, Issue 6, Page(s) 495–499

    Abstract: Among the many molecular entities suitable for therapeutic use, peptides have emerged as a particularly attractive option for academic drug discovery and development. Their modular structure and extendibility, the availability of powerful and affordable ... ...

    Abstract Among the many molecular entities suitable for therapeutic use, peptides have emerged as a particularly attractive option for academic drug discovery and development. Their modular structure and extendibility, the availability of powerful and affordable screening platforms, and the relative ease-of-synthesis render therapeutic peptides highly approachable for teaching and research alike. With a strong focus on the therapeutic modulation of host defence pathways, including the complement and renin-angiotensin systems, the Molecular Pharmacy group at the University of Basel strongly relies on peptides to introduce students to practical aspects of modern drug design, to discover novel therapeutics for immune and inflammatory diseases, and to expand on options for the preclinical development of a promising drug class. Current projects reach from student-driven iterative design of peptidic angiotensin-converting enzyme inhibitors and the use of phage display technology to discover novel immune modulators to the development of protective peptide coatings for biomaterials and transplants and the structure-activity-relationship-guided optimization of therapeutic peptide drug candidates in late-stage clinical trials. Even at the current stage, peptides allow for a perfect circle between pharmaceutical research and education, and the recent spark of clinical applications for peptide-based drugs may only increase the value and relevance of this versatile drug class.
    Language English
    Publishing date 2021-07-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1516-7
    ISSN 0009-4293
    ISSN 0009-4293
    DOI 10.2533/chimia.2021.495
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Manipulating the mediator: modulation of the alternative complement pathway C3 convertase in health, disease and therapy.

    Ricklin, Daniel

    Immunobiology

    2012  Volume 217, Issue 11, Page(s) 1057–1066

    Abstract: The complement network is increasingly recognized as an important triage system that is able to differentiate between healthy host cells, microbial intruders, cellular debris and immune complexes, and tailor its actions accordingly. At the center of this ...

    Abstract The complement network is increasingly recognized as an important triage system that is able to differentiate between healthy host cells, microbial intruders, cellular debris and immune complexes, and tailor its actions accordingly. At the center of this triage mechanism is the alternative pathway C3 convertase (C3bBb), a potent enzymatic protein complex capable of rapidly converting the inert yet abundant component C3 into powerful effector fragments (C3a and C3b), thereby amplifying the initial response on unprotected surfaces and inducing a variety of effector functions. A fascinating molecular mechanism of convertase assembly and intrinsic regulation, as well as the interplay with a panel of cell surface-bound and soluble inhibitors are essential for directing complement attack to intruders and protecting healthy host cells. While efficiently keeping immune surveillance and homeostasis on track, the reliance on an intricate cascade of interaction and conversion steps also renders the C3 convertase vulnerable to derail. On the one hand, tissue damage, accumulation of debris, or polymorphisms in complement genes may unfavorably shift the balance between activation and regulation, thereby contributing to a variety of clinical conditions. On the other hand, pathogens developed powerful evasion strategies to avoid complement attack by targeting the convertase. Finally, we increasingly challenge our bodies with foreign materials such as biomaterial implants or drug delivery vehicles that may induce adverse effects that are at least partially caused by complement activation and amplification via the alternative pathway. The involvement of the C3 convertase in a range of pathological conditions put this complex into the spotlight of complement-targeted drug discovery efforts. Fortunately, the physiological regulation and microbial evasion approaches provide a rich source of inspiration for the development of powerful treatment options. This review provides insight into the current knowledge about the molecular mechanisms that drive C3 convertase activity, reveals common and divergent strategies of convertase inhibition employed by host and pathogens, and how this inhibitory arsenal can be tapped for developing therapeutic options to treat complement-related diseases.
    MeSH term(s) Animals ; Autoimmune Diseases/drug therapy ; Autoimmune Diseases/immunology ; Complement C3/immunology ; Complement C3/metabolism ; Complement C3 Convertase, Alternative Pathway/antagonists & inhibitors ; Complement C3 Convertase, Alternative Pathway/metabolism ; Complement Pathway, Alternative ; Drug Discovery ; Humans ; Immune Evasion ; Infections/drug therapy ; Infections/immunology ; Inflammation/drug therapy ; Inflammation/immunology ; Molecular Targeted Therapy
    Chemical Substances Complement C3 ; Complement C3 Convertase, Alternative Pathway (EC 3.4.21.47)
    Language English
    Publishing date 2012-08-07
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 563292-4
    ISSN 1878-3279 ; 0171-2985
    ISSN (online) 1878-3279
    ISSN 0171-2985
    DOI 10.1016/j.imbio.2012.07.016
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  10. Article ; Online: From discovery to approval: A brief history of the compstatin family of complement C3 inhibitors.

    Mastellos, Dimitrios C / Ricklin, Daniel / Sfyroera, Georgia / Sahu, Arvind

    Clinical immunology (Orlando, Fla.)

    2021  Volume 235, Page(s) 108785

    Abstract: The FDA approval of pegcetacoplan (Empaveli), a PEGylated compstatin-based C3 therapeutic, as a new treatment for paroxysmal nocturnal hemoglobinuria (PNH) marks a milestone in the history of complement drug discovery. Almost 15 years after the approval ... ...

    Abstract The FDA approval of pegcetacoplan (Empaveli), a PEGylated compstatin-based C3 therapeutic, as a new treatment for paroxysmal nocturnal hemoglobinuria (PNH) marks a milestone in the history of complement drug discovery. Almost 15 years after the approval of the first complement-specific drug for PNH, the anti-C5 antibody eculizumab, a novel class of complement inhibitors with a distinct mechanism of action finally enters the clinic. This landmark decision broadens the spectrum of available complement therapeutics, offering patients with unmet clinical needs or insufficient responses to anti-C5 therapy an alternative treatment option with a broad activity profile. Here we present a brief historical account of this newly approved complement drug, consolidating its approval within the long research record of the compstatin family of peptidic C3 inhibitors.
    MeSH term(s) Complement C3/antagonists & inhibitors ; Complement C3/metabolism ; Drug Approval ; Gene Expression Regulation/drug effects ; Hemoglobinuria, Paroxysmal/drug therapy ; Humans ; Peptides, Cyclic/chemistry ; Peptides, Cyclic/pharmacology
    Chemical Substances Complement C3 ; Peptides, Cyclic ; compstatin ; pegcetacoplan (TO3JYR3BOU)
    Language English
    Publishing date 2021-06-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1459903-x
    ISSN 1521-7035 ; 1521-6616
    ISSN (online) 1521-7035
    ISSN 1521-6616
    DOI 10.1016/j.clim.2021.108785
    Database MEDical Literature Analysis and Retrieval System OnLINE

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