A
Menu
First published October 13, 2025 Granted Aachen patent C – Chemistry & metallurgy

SELECTION AND CHARACTERIZATION OF A PEPTIDE-BASED COMPLEMENT ACTIVATOR

Espacenet Family 91073285

Abstract

[0001] The present invention relates to complement component C1q binders (“C1q binders”) comprising a peptide that binds to a globular head domain of complement component C1q and by this can either activate or inhibit complement. Further disclosed are pharmaceutical compositions and kits comprising the C1q binders according to the invention. The invention a|so relates to the medical uses of such C1q binders and compositions. In particular, the C1q binders or compositions of the invention may be used in the treatment, prevention and diagnosis of diseases or disorders. The invention a|so relates to nuc|eic acids encoding the peptides.

Inventors 4

  1. Matthias, Wilhelmus René Hamers
  2. Thomas, Harry Sharp
  3. Leoni, Abendstein
  4. Aimee, Boyle

Inventors are linked to an Aachen author when surname and first name match exactly one author.

Applicants

  • ACADEMISCH ZIEKENHUIS LEIDEN (H.O.D.N.LUMC) GBS Leiden

Cited papers 15 in the database

Non-patent literature as cited (70)
  • - SINGLETONSAINSBURY: "Dictionary of Microbiology and Molecular Biology", 1994, JOHN WILEY AND SONS
  • - L. NORDERHAUG ET AL.: "Chimeric mouse human IgG3 antibodies with an IgG4-like hinge region induce complement-mediated lysis more efficiently than IgG3 with normal hing", EUROPEAN JOURNAL OF IMMUNOLOGY, vol. 21, 1991, pages 2379 - 2384
  • - NEEDLEMAN ET AL., J. MOL. BIOL., vol. 48, 1970, pages 444 - 453
  • - MEYERS ET AL., CABIOS, vol. 4, 1989, pages 11 - 17
  • - ALTSCHUL ET AL., J. MOL. BIOL., vol. 215, 1990, pages 403 - 410
  • - ALTSCHUL ET AL., NUCL. ACIDS RES., vol. 25, 1997, pages 3389 - 3402
  • - S. FOSS ET AL.: "Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria", NATURE COMMUNICATIONS, vol. 15, 2007
  • - CHARLTON: "Methods in Molecular Biology", vol. 248, 2003, HUMANA PRESS, pages: 245 - 254
  • - GERNGROSS, NAT. BIOTECH., vol. 22, 2004, pages 1409 - 1414
  • - LI ET AL., NAT. BIOTECH., vol. 24, 2006, pages 210 - 215
  • - MATHER, BIOL. REPROD., vol. 23, 1980, pages 243 - 251
  • - MATHER ET AL., ANAL. N.Y. ACAD. SCI., vol. 383, 1982, pages 44 - 68
  • - URLAUB ET AL., PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4216
  • - C. S. ZENT ET AL.: "Alemtuzumab (CAM PATH 1H) does not kill chronic lymphocytic leukemia cells in serum free medium", LEUKEMIA RESEARCH, vol. 248, 2004, pages 495 - 507
  • - ABENDSTEIN ET AL.: "DNA nanostructure-templated antibody complexes provide insights into the geometric requirements of human complement cascade activation", BIORXIV, October 2023 (2023-10-01)
  • - SAMBROOK ET AL.: "Molecular Cloning - a laboratory manual", 1989, COLD SPRING HARBOR PRESS
  • - T. DAMELANG ET AL.: "The Influence of Human IgG Subclass and Allotype on Complement Activation", THE JOURNAL OF IMMUNOLOGY, vol. 211, 2023, pages 1725 - 1735
  • - T. H. SHARP ET AL.: "Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 116, 2019, pages 11900 - 11905
  • - K. D. BORNEMANN ET AL.: "Roles of heavy and light chains in IgM polymerization", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 92, 1995, pages 4912 - 4916
  • - D. UGURLAR ET AL.: "Structures of C1-lgG1 provide insights into how danger pattern recognition activates complement", SCIENCE, vol. 359, 2018, pages 794 - 797, XP055617949, DOI: 10.1126/science.aao4988
  • - L. ABENDSTEIN ET AL.: "Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains", NATURE COMMUNICATIONS, vol. 14, 2023, pages 4027
  • - C. A. DIEBOLDER ET AL.: "Complement is activated by IgG hexamers assembled at the cell surface", SCIENCE, vol. 343, 2014, pages 1260 - 1263, XP055268751, DOI: 10.1126/science.1248943
  • - D. C. MASTELLOSG. HAJISHENGALLISJ. D. LAMBRIS: "A guide to complement biology, pathology and therapeutic opportunity", NATURE REVIEWS IMMUNOLOGY, vol. 24, 2024, pages 118 - 141
  • - J. R. DUNKELBERGERW.-C. SONG: "Complement and its role in innate and adaptive immune responses", CELL RESEARCH, vol. 20, 2010, pages 34 - 50
  • - G. PETER, J. T. ANDREA, E. M. TOM: " Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics.", PHARMACOLOGICAL REVIEWS, vol. 73, 2021, pages 792, XP055945241, DOI: 10.1124/pharmrev.120.000072
  • - J. A. SHARPP. H. WHITLEYK. M. CUNNIONN. K. KRISHNA: "Peptide inhibitor of complement C1, a novel suppressor of classical pathway activation: Mechanistic studies and clinical potential", FRONTIERS IN IMMUNOLOGY, vol. 5, 2014, pages 1 - 9, XP055364649, DOI: 10.3389/fimmu.2014.00406
  • - J. A. SHARP ET AL.: "Peptide Inhibitor of Complement C1 (PIC1) Rapidly Inhibits Complement Activation after Intravascular Injection in Rats", PLOS ONE, vol. 10, 2015, pages e0132446
  • - C. LAMERSD. C. MASTELLOSD. RICKLINJ. D. LAMBRIS: "Compstatins: the dawn of clinical C3-targeted complement inhibition", TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 43, 2022, pages 629 - 640, XP087119378, DOI: 10.1016/j.tips.2022.01.004
  • - J. F. HOWARD JR ET AL.: "Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody-Positive Generalized Myasthenia Gravis", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 30, 2021, pages 483 - 493, XP093067685, DOI: 10.1080/13543784.2021.1897567
  • - P. KUMARP. HAIRK. CUNNIONN. KRISHNAT. BASS: "Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model", PLOS ONE, vol. 16, 2021, pages e0257960
  • - J. S. NAIR SS: "Novel Immunotherapies for Myasthenia Gravis", IMMUNOTARGETS THER., vol. 12, 2023, pages 25 - 45
  • - M. DE WEERS ET AL.: "Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors", THE JOURNAL OF IMMUNOLOGY, vol. 186, 2011, pages 1840 - 1848, XP055210884, DOI: 10.4049/jimmunol.1003032
  • - J. GOLAY: "Direct targeting of cancer cells with antibodies: What can we learn from the successes and failure of unconjugated antibodies for lymphoid neoplasias?", JOURNAL OF AUTOIMMUNITY, vol. 85, 2017, pages 6 - 19, XP085252803, DOI: 10.1016/j.jaut.2017.06.002
  • - R. P. TAYLORM. A. LINDORFER: "Cytotoxic mechanisms of immunotherapy: Harnessing complement in the action of anti-tumor monoclonal antibodies", SEMINARS IN IMMUNOLOGY, vol. 28, 2016, pages 309 - 316, XP029684742, DOI: 10.1016/j.smim.2016.03.003
  • - R. N. DE JONG ET AL.: ", A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface", PLOS BIOLOGY, vol. 14, 2016, pages e1002344
  • - S. C. OOSTINDIE ET AL.: "Logic-gated antibody pairs that selectively act on cells co-expressing two antigens", NATURE BIOTECHNOLOGY, vol. 40, 2022, pages 1509 - 1519
  • - D. V. PEDERSEN ET AL.: "Bispecific Complement Engagers for Targeted Complement Activation", THE JOURNAL OF IMMUNOLOGY, vol. 211, 2023, pages 403 - 413
  • - M. L. PEDERSEN ET AL.: "Nanobody-mediated complement activation to kill HIV-infected cells", EMBO MOLECULAR MEDICINE, vol. 15, 2023
  • - N. S. LAURSEN ET AL.: "Functional and Structural Characterization of a Potent C1q Inhibitor Targeting the Classical Pathway of the Complement System", FRONTIERS IN IMMUNOLOGY, vol. 11, 2020, pages 1 - 15
  • - C. MOREAU ET AL.: "Structural and functional characterization of a single-chain form of the recognition domain of complement protein C1q", FRONTIERS IN IMMUNOLOGY, vol. 7, 2016, pages 1 - 9
  • - M. J. VAN HAREN ET AL.: "Macrocyclic peptides as allosteric inhibitors of nicotinamide: N-methyltransferase (NNMT", RSC CHEMICAL BIOLOGY, vol. 2, 2021, pages 1546 - 1555
  • - V. THIJSSEN ET AL.: "A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 120, 2023, pages e2303292120
  • - M. J. VAN HAREN ET AL.: "Macrocyclic Peptides as Allosteric Inhibitors of Nicotinamide N-Methyltransferase (NNMT", CHEMRXIV, 2020, pages 1 - 19
  • - H. ZHANGS. CHEN: "Cyclic peptide drugs approved in the last two decades", RSC CHEMICAL BIOLOGY, vol. 3, 2001, pages 18 - 31
  • - L. C. WIJEYEWICKREMA ET AL.: "Molecular determinants of the substrate specificity of the complement-initiating protease, C1r", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 288, 2013, pages 15571 - 15580
  • - S. IMANISHI ET AL.: "In Vitro Selection of Macrocyclic d/l-Hybrid Peptides against Human EGFR", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 143, 2021, pages 5680 - 5684
  • - Y. GOTOH. SUGA: "The RaPID Platform for the Discovery of Pseudo-Natural Macrocyclic Peptides", ACCOUNTS OF CHEMICAL RESEARCH, vol. 54, 2021, pages 3604 - 3617, XP093007366, DOI: 10.1021/acs.accounts.1c00391
  • - C. MOLDH. GEWURZT. W. DU CLOS: "Regulation of complement activation by C-reactive protein", IMMUNOPHARMACOLOGY, vol. 42, 1999, pages 23 - 30
  • - A. P. SJDBERGL. A. TROUWA. M. BLOM: "Complement activation and inhibition: a delicate balance", TRENDS IN IMMUNOLOGY, vol. 30, 2009, pages 83 - 90, XP025959598, DOI: 10.1016/j.it.2008.11.003
  • - L. T. ROUMENINA: "Interaction of C1q with IgG1, C-reactive Protein and Pentraxin 3: Mutational Studies Using Recombinant Globular Head Modules of Human C1q A, B, and C Chains.", BIOCHEMISTRY, vol. 45, 2006, pages 4093 - 4104
  • - N. DYLAN ET AL.: "Structural basis for surface activation of the classical complement cascade by the short pentraxin C-reactive protein", BIORXIV, 2024
  • - S. M. KONDENGADAN ET AL.: "Click chemistry and drug delivery: A bird's-eye view", ACTA PHARMACEUTICA SINICA B, vol. 13, 2023, pages 1990 - 2016
  • - J. SCHWOCHERT ET AL.: "Stereochemistry Balances Cell Permeability and Solubility in the Naturally Derived Phepropeptin Cyclic Peptides", ACS MEDICINAL CHEMISTRY LETTERS, vol. 7, 2016, pages 757 - 761
  • - D. J. DIJKSTRA ET AL.: "Human anti-C1q autoantibodies bind specifically to solid-phase C1q and enhance phagocytosis but not complement activation", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 120, 2023, pages e2310666120, XP093129323
  • - A. VALERIEVA ET AL.: "Recombinant human C1 esterase inhibitor for hereditary angioedema attacks: A European registry", WORLD ALLERGY ORGANIZATION JOURNAL, vol. 14, 2021, pages 100535
  • - A. ROTH ET AL.: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial", BLOOD, vol. 140, 2022, pages 980 - 991
  • - J. W. LEE ET AL.: "Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study", BLOOD, vol. 133, 2019, pages 530 - 539
  • - L. LUCIOR. ANTONIO MARIAN. ROSARIO: "Paroxysmal nocturnal hemoglobinuria and eculizumab", HAEMATOLOGICA, vol. 95, 2010, pages 523 - 526
  • - D. R. W. JAYNEP. A. MERKELT. J. SCHALLP. BEKKER: "Avacopan for the Treatment of ANCA-Associated Vasculitis", NEW ENGLAND JOURNAL OF MEDICINE, vol. 384, 2021, pages 599 - 609, XP093154275, DOI: 10.1056/NEJMoa2023386
  • - A. C. SAMPSON ET AL.: "Peptide inhibition of acute lung injury in a novel two-hit rat model", PLOS ONE, vol. 16, 2021, pages e0259133
  • - N. K. KRISHNAK. M. CUNNIONG. A. PARKER: "The EPICC Family of Anti-Inflammatory Peptides: Next Generation Peptides, Additional Mechanisms of Action, and In Vivo and Ex Vivo Efficacy", FRONTIERS IN IMMUNOLOGY, vol. 13, 2022
  • - A. ROOS ET AL.: "Specific Inhibition of the Classical Complement Pathway by C1q-Binding Peptides", THE JOURNAL OF IMMUNOLOGY, vol. 167, 2001, pages 7052 - 7059, XP001056046
  • - F. M. A. R. A. T: "Signaling properties of CR3 (CD11b/CD18) and CR1 (CD35) in relation to phagocytosis of complement-opsonized particles", JOURNAL OF IMMUNOLOGY (BALTIMORE, MD., vol. 151, 1993, pages 330 - 338
  • - G. DEKKERS ET AL.: "Decoding the Human Immunoglobulin G-Glycan Repertoire Reveals a Spectrum of Fc-Receptor- and Complement-Mediated-Effector Activities", FRONTIERS IN IMMUNOLOGY, vol. 8, 2017
  • - B. PESCHKEC. W. KELLERP. WEBERI. QUASTJ. D. LUNEMANN: "Fc-galactosylation of human immunoglobulin gamma isotypes improves C1q binding and enhances complement-dependent cytotoxicity", FRONTIERS IN IMMUNOLOGY, vol. 8, 2017, XP055964362, DOI: 10.3389/fimmu.2017.00646
  • - A. NATSUME ET AL.: "Engineered Antibodies of IgG1/IgG3 Mixed Isotype with Enhanced Cytotoxic Activities", CANCER RESEARCH, vol. 68, 2008, pages 3863 - 3872, XP007913550, DOI: 10.1158/0008-5472.CAN-07-6297
  • - G. L. MOOREH. CHENS. KARKIG. A. LAZAR: "Engineered Fc variant antibodies with enhanced ability to recruit complement and mediate effector functions", MABS, vol. 2, 2010, pages 181 - 189
  • - D. P. NOONET. T. VAN DER VELDENT. H. SHARP: "Cryo-Electron Microscopy and Biochemical Analysis Offer Insights Into the Effects of Acidic pH, Such as Occur During Acidosis, on the Complement Binding Properties of C-Reactive Protein", FRONTIERS IN IMMUNOLOGY, vol. 12, 2021
  • - Y. GOTO ET AL.: "Reprogramming the Translation Initiation for the Synthesis of Physiologically Stable Cyclic Peptides", ACS CHEMICAL BIOLOGY, vol. 3, 2008, pages 120 - 129, XP002564832, DOI: 10.1021/cb700233t
  • - ROOS A ET AL: "SPECIFIC INHIBITION OF THE CLASSICAL COMPLEMENT PATHWAY BY C1Q-BINDING PEPTIDES", THE JOURNAL OF IMMUNOLOGY, WILLIAMS & WILKINS CO, US, vol. 167, no. 12, 15 December 2001 (2001-12-15), pages 7052 - 7059, XP001056046, ISSN: 0022-1767

Cited patents 8

US5648237A US5789199A US5840523A US5959177A US6040498A US6420548B1 US7125978B1 US6417429B1