Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses

  1. Bermejo, Iris A. 4
  2. Guerreiro, Ana 2
  3. Eguskiza, Ander 1
  4. Martínez-Sáez, Nuria 411
  5. Lazaris, Foivos S. 4
  6. Asín, Alicia 4
  7. Somovilla, Víctor J. 4
  8. Compañón, Ismael 4
  9. Raju, Tom K. 5
  10. Tadic, Srdan 5
  11. Garrido, Pablo 5
  12. García-Sanmartín, Josune 5
  13. Mangini, Vincenzo 12
  14. Grosso, Ana S. 910
  15. Marcelo, Filipa 910
  16. Avenoza, Alberto 4
  17. Busto, Jesús H. 4
  18. García-Martín, Fayna 4
  19. Hurtado-Guerrero, Ramón 678
  20. Peregrina, Jesús M. 4
  21. Bernardes, Gonçalo J. L. 23
  22. Martínez, Alfredo 5
  23. Fiammengo, Roberto 112
  24. Corzana, Francisco 4
  1. 1 Department of Biotechnology, University of Verona, Verona 37134, Italy
  2. 2 Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa 1649-028, Portugal
  3. 3 Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  4. 4 Department of Chemistry and Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Universidad de La Rioja, Logroño 26006, Spain
  5. 5 Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño 26006, Spain
  6. 6 Institute of Biocomputation and Physics of Complex Systems, University of Zaragoza, Zaragoza 50018, Spain
  7. 7 Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200, Denmark
  8. 8 Fundación ARAID, Zaragoza 50018, Spain
  9. 9 Applied Molecular Biosciences Unit UCIBIO, Department of Chemistry, NOVA School of Science and Technology, Caparica 2829-516, Portugal
  10. 10 Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, Caparica 2829-516, Portugal
  11. 11 Departamento de Tecnología y Química Farmacéuticas, Universidad de Navarra, Pamplona 31008, Spain
  12. 12 Center for Biomolecular Nanotechnologies@UniLe, Istituto Italiano di Tecnologia (IIT), Arnesano, Lecce 73010, Italy
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Revista:
JACS Au

ISSN: 2691-3704,  2691-3704

Año de publicación: 2023

Tipo: Artículo

DOI: 10.1021/JACSAU.3C00587 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: JACS Au

Repositorio institucional: lock_openAcceso abierto Editor

Resumen

Mucin-1(MUC1)glycopeptidesareexceptionalcandidatesforpotentialcancervaccines.However,theirautoantigenicnatureoftenresultsinaweakimmuneresponse.Toovercomethisdrawback,wecarefullyengineeredsyntheticantigenswithprecisechemicalmodifications.Tobeeffectiveandstimulateananti-MUC1response,artificialantigensmustmimictheconforma-tionaldynamicsofnaturalantigensinsolutionandhaveanequivalentorhigherbindingaffinitytoanti-MUC1antibodiesthantheirnaturalcounterparts.Asa proofofconcept,wehavedevelopeda glycopeptidethatcontainsnoncanonicalaminoacid(2S,3R)-3-hydroxynorvaline.Theunnaturalantigenfulfillsthesetwopropertiesandeffectivelymimicsthethreonine-derivedantigen.Ontheonehand,conformationalanalysisinwatershowsthatthissurrogateexploresalandscapesimilartothatofthenaturalvariant.Ontheotherhand,thepresenceofanadditionalmethylenegroupinthesidechainofthisanalogcomparedtothethreonineresidueenhancesa CH/πinteractionintheantigen/antibodycomplex.Despiteanenthalpy−entropybalance,thissyntheticglycopeptidehasabindingaffinityslightlyhigherthanthatofitsnaturalcounterpart.Whenconjugatedwithgoldnanoparticles,thevaccinecandidatestimulatestheformationofspecificanti-MUC1IgGantibodiesinmiceandshowsefficacycomparabletothatofthenaturalderivative.Theantibodiesalsoexhibitcross-reactivitytoselectivelytarget,forexample,humanbreastcancercells.Thisinvestigationreliedonnumerousanalytical(e.g.,NMRspectroscopyandX-raycrystallography)andbiophysicaltechniquesandmoleculardynamicssimulationstocharacterizetheantigen−antibodyinteractions.Thisworkflowstreamlinesthesyntheticprocess,savestime,andreducestheneedforextensive,animal-intensiveimmunizationprocedures.Theseadvancesunderscorethepromiseofstructure-basedrationaldesignintheadvanceofcancer

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