Methyl-to-Ethyl Replacement Makes the Difference: Structure-Guided Design of a New Cancer Vaccine Based on a Tn An-gen Surrogate

  1. Foivos S. Lazaris 1
  2. Iris A. Bermejo 1
  3. Ana Guerreiro 2
  4. A. Avenoza Aznar 1
  5. J.H. Busto Sancirián 1
  6. F M. García Martín 1
  7. Gonçalo J. L. Bernardes 23
  8. R. Hurtado-Guerrero 4
  9. Roberto Fiammengo 5
  10. A. Martínez Ramírez 6
  11. J.M. Peregrina García 1
  12. F. Corzana López 1
  1. 1 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  2. 2 Universidade de Lisboa
    info

    Universidade de Lisboa

    Lisboa, Portugal

    ROR https://ror.org/01c27hj86

  3. 3 University of Cambridge
    info

    University of Cambridge

    Cambridge, Reino Unido

    ROR https://ror.org/013meh722

  4. 4 Universidad de Zaragoza
    info

    Universidad de Zaragoza

    Zaragoza, España

    ROR https://ror.org/012a91z28

  5. 5 University of Verona
    info

    University of Verona

    Verona, Italia

    ROR https://ror.org/039bp8j42

  6. 6 Centro de Investigación Biomédica de La Rioja
    info

    Centro de Investigación Biomédica de La Rioja

    Logroño, España

    ROR https://ror.org/03vfjzd38

Show affiliations +
Proceedings:
VI RSEQ Chemical Biology Group Meeting - ChemBio VI

Year of publication: 2023

Congress: VI RSEQ Chemical Biology Group Meeting - ChemBio VI (6º. 2023. Valencia)

Type: Conference Poster

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Abstract

Mucins are large extracellular glycoproteins that exhibit different glycosylation patterns and post-translational modifications between healthy and cancer cells[1]. Mucin 1 (MUC1) is a common glycoprotein in cancer cells that plays a multifaceted role in cancer development, cell proliferation, and migration[2,3]. These properties make MUC1 an excellent antigen for cancer vaccine candidates. Several works[3,4] have used MUC1-derived GalNAc glycopeptides, especially the sequence APDT(α-O-GalNAc-Thr)RP, for cancer vaccine development but with limited success due to the low immunogenicity and stability of the glycopeptide. We have developed a novel Tn antigen following a structure-guided design in which the threonine of the above sequence has been replaced by the unnatural amino acid L-4-hydroxynorvaline (Hnv) to increase the antigen/antibody affinity. We have confirmed by X-crystallography analysis of the complex that the ethyl group at the Cβ of the unnatural residue favors the CH/π interactions between the Tn antigen and the SM3 antibody, resulting in a slight increase in affinity due to enthalpy-entropy balance. The chemical modification (HnvThr) allows the synthetic glycopeptide to exhibit similar properties to the naturally occurring derivative, similar serum stability, and a similar conformational landscape in solution. A vaccination campaign in mice is currently underway in which the synthetic antigen has been conjugated to evaluate the biological impact of this chemical modification.