A trypanosome-derived immunotherapeutics platform elicits potent high-affinity antibodies, negating the effects of the synthetic opioid fentanyl.
| Title: | A trypanosome-derived immunotherapeutics platform elicits potent high-affinity antibodies, negating the effects of the synthetic opioid fentanyl. |
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| Authors: | Triller G; Division of Immune Diversity, German Cancer Research Center, 69120 Heidelberg, Germany.; Vlachou EP; Division of Immune Diversity, German Cancer Research Center, 69120 Heidelberg, Germany; Panosome GmbH, 69123 Heidelberg, Germany.; Hashemi H; Division of Immune Diversity, German Cancer Research Center, 69120 Heidelberg, Germany.; van Straaten M; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, 69120 Heidelberg, Germany.; Zeelen JP; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, 69120 Heidelberg, Germany.; Kelemen Y; Hepione Therapeutics, Inc., New York, NY 10014, USA.; Baehr C; Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.; Marker CL; Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Iuvo Bioscience, Rush, NY 14543, USA.; Ruf S; Division of Immune Diversity, German Cancer Research Center, 69120 Heidelberg, Germany.; Svirina A; Division of Immune Diversity, German Cancer Research Center, 69120 Heidelberg, Germany.; Chandra M; Panosome GmbH, 69123 Heidelberg, Germany; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, 69120 Heidelberg, Germany.; Urban K; Division of Immune Diversity, German Cancer Research Center, 69120 Heidelberg, Germany.; Gkeka A; Division of Immune Diversity, German Cancer Research Center, 69120 Heidelberg, Germany; Panosome GmbH, 69123 Heidelberg, Germany.; Kruse S; Panosome GmbH, 69123 Heidelberg, Germany.; Baumann A; Cancer Drug Development Group, German Cancer Research Center, 69120 Heidelberg, Germany.; Miller AK; Cancer Drug Development Group, German Cancer Research Center, 69120 Heidelberg, Germany.; Bartel M; Forensic Toxicology, Institute of Forensic and Traffic Medicine, Heidelberg University Hospital, 69115 Heidelberg, Germany.; Pravetoni M; Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Psychiatry and Behavioral Sciences, Department of Pharmacology, University of Washington School of Medicine, Center for Medication Development for Substance Use Disorders, Seattle, WA 98195, USA.; Stebbins CE; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, 69120 Heidelberg, Germany.; Papavasiliou FN; Division of Immune Diversity, German Cancer Research Center, 69120 Heidelberg, Germany.; Verdi JP; Division of Immune Diversity, German Cancer Research Center, 69120 Heidelberg, Germany; Hepione Therapeutics, Inc., New York, NY 10014, USA. Electronic address: j.verdi@dkfz-heidelberg.de. |
| Source: | Cell reports [Cell Rep] 2023 Feb 28; Vol. 42 (2), pp. 112049. Date of Electronic Publication: 2023 Jan 30. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Cambridge, MA] : Cell Press, c 2012- |
| MeSH Terms: | Trypanosoma brucei brucei*/genetics ; Trypanosomiasis, African*/drug therapy ; Trypanosoma*; Fentanyl/pharmacology ; Fentanyl/therapeutic use ; Animals ; Mice ; Analgesics, Opioid ; Variant Surface Glycoproteins, Trypanosoma ; Immunotherapy |
| Abstract: | Poorly immunogenic small molecules pose challenges for the production of clinically efficacious vaccines and antibodies. To address this, we generate an immunization platform derived from the immunogenic surface coat of the African trypanosome. Through sortase-based conjugation of the target molecules to the variant surface glycoprotein (VSG) of the trypanosome surface coat, we develop VSG-immunogen array by sortase tagging (VAST). VAST elicits antigen-specific memory B cells and antibodies in a murine model after deploying the poorly immunogenic molecule fentanyl as a proof of concept. We also develop a single-cell RNA sequencing (RNA-seq)-based computational method that synergizes with VAST to specifically identify memory B cell-encoded antibodies. All computationally selected antibodies bind to fentanyl with picomolar affinity. Moreover, these antibodies protect mice from fentanyl effects after passive immunization, demonstrating the ability of these two coupled technologies to elicit therapeutic antibodies to challenging immunogens.; (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests G.T., C.E.S., F.N.P., and J.P.V. report being shareholders of Panosome GmbH and Hepione Therapeutics and having patents planned, pending, or issued broadly relevant to the work. C.E.S. and F.N.P. report being the managing directors of Panosome GmbH. S.K. reports being a shareholder of Panosome GmbH and Hepione Therapeutics. S.R. and K.U. report being employees of Panosome GmbH. P.V., K.U., M.v.S., J.P.Z., Y.K., A.S., A.K.M, A.B., and H.H. report having patents planned, pending, or issued broadly relevant to the work. M.P. and C.B. have patents pending related to fentanyl haptens, conjugates, and mAbs against fentanyl-like compounds. |
| Grant Information: | R01 AI097127 United States AI NIAID NIH HHS; R43 DA052960 United States DA NIDA NIH HHS |
| Contributed Indexing: | Keywords: CP: Immunology; Trypanosoma brucei; antibody repertoire analysis; fentanyl; humoral immunity; immunological memory; opioid overdose; sortase; variant surface glycoprotein |
| Substance Nomenclature: | 0 (Analgesics, Opioid); UF599785JZ (Fentanyl); 0 (Variant Surface Glycoproteins, Trypanosoma) |
| Entry Date(s): | Date Created: 20230131 Date Completed: 20231004 Latest Revision: 20231024 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10387133 |
| DOI: | 10.1016/j.celrep.2023.112049 |
| PMID: | 36719797 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't