Discovery of a fully human antibody to the proximal membrane terminus of MUC1 based on a B-cell high-throughput screening technique.

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  • Author(s): Wu Y;Wu Y;Wu Y;Wu Y; Ji X; Ji X; Yang Y; Yang Y; Yang Y; Wu B; Wu B
  • Source:
    International immunopharmacology [Int Immunopharmacol] 2024 Dec 05; Vol. 142 (Pt B), pp. 113204. Date of Electronic Publication: 2024 Sep 23.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 100965259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1705 (Electronic) Linking ISSN: 15675769 NLM ISO Abbreviation: Int Immunopharmacol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam ; New York : Elsevier Science, c2001-
    • Subject Terms:
      High-Throughput Screening Assays*/methods ; Mucin-1*/immunology ; Mucin-1*/genetics; Humans ; Animals ; Mice ; Cell Line, Tumor ; B-Lymphocytes/immunology ; Mice, Knockout ; Cross Reactions ; Female ; Endocytosis ; Antibodies, Monoclonal/immunology ; Breast Neoplasms/immunology ; Oligopeptides
    • Abstract:
      Mucin 1 plays an important role in tumor signaling and is overexpressed in adenocarcinoma and the digestive system. Many antibodies have been developed against MUC1 targets. Previously developed antibodies were mainly directed against distal membrane-terminal MUC1-N, but distal membrane-terminal MUC1-N is shed during cell growth and therefore binds to antibodies developed against tandem repeat sequences and becomes ineffective. Here, we provide a simple and rapid method for preparing antibodies targeting the proximal membrane end of MUC1. Immunological target antigens were designed based on Biocytogen Renlite KO mice. With the help of B-cell high-throughput screening technology, we rapidly screened and prepared fully human antibodies with human-macaque cross-reactivity, high affinity, high specificity, and endocytosis. Using this method, we screened 40 antibodies with human-monkey cross-reactivity, which specifically recognized breast cancer cell lines with human and monkey affinities ranging from (1.04E-07-2.91E-09). Of these, the antibodies with germline genes IGHV4-59*01 and IGHV3-30*03 had nanomolar affinities, with high endocytosis effects in breast cancer cells. Ab.07 (IGHV3-30*03) coupled with monomethyl auristatin E (MMAE) showed good anti-tumor activity in different tumor cells. In summary, we describe a method for designing and producing excellent antibodies that can be assembled into antibody-drug conjugates and bispecific antibodies by proximal-membrane-end immunization and B-cell high-throughput screening that can rapidly generate high-quality antibodies.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Antibody discovery; B-cell high-throughput screening; Fully human antibody; MUC1 proximal membrane end
    • Accession Number:
      0 (Mucin-1)
      V7I58RC5EJ (monomethyl auristatin E)
      0 (MUC1 protein, human)
      0 (Antibodies, Monoclonal)
      0 (Oligopeptides)
    • Publication Date:
      Date Created: 20240924 Date Completed: 20241011 Latest Revision: 20241011
    • Publication Date:
      20241011
    • Accession Number:
      10.1016/j.intimp.2024.113204
    • Accession Number:
      39317052