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<p>Folate receptor alpha (FRα), a membrane protein involved in folate transport, is a promising therapeutic target for ovarian cancer and other malignancies. The murine Monoclonal antibody (MAb) MOv19, developed in our lab, has pioneered the development of chimeric antibody-drug conjugates currently approved or in clinical trials for the treatment of FRα-positive cancers. To further reduce antibody’s immunogenicity, we engineered and characterized a new fully human IgG1 antibody (AFRA hIgG1) to FRα starting from MOv19. AFRA hIgG1 was constructed and characterized for binding affinity, specificity to purified FRα and various FRα-expressing tumor cells and ability to recruit effector cells in vitro in comparison to the chimeric version of MOv19 (ChiMOv19). AFRA hIgG1 and ChiMOv19 have comparable functional affinities being 10<sup>−9</sup> M and 10<sup>−10</sup> M, respectively although AFRA hIgG1 has an intrinsic constant affinity 10<sup>3</sup> lower than that of ChiMOv19, 2.6 × 10<sup>−7</sup> M vs. 3.5 × 10<sup>−10</sup> M, respectively. Furthermore, AFRA hIgG1 demonstrated a better binding kinetic with an overall efficacy comparable to ChiMOv19 in recruiting effector cell functions. These findings highlight that functional affinity, rather than intrinsic affinity, is a key determinant of biological response. AFRA hIgG1 shows promise as a biologic agent for the treatment of FRα-positive cancers.</p>

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Novel fully human IgG1 targeting folate receptor α demonstrates antitumor efficacy driven by avidity rather than monovalent binding affinity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月31日

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  • Elena Pinto,
  • Davide Tresoldi,
  • Valeria Arlotta,
  • Elena Luison,
  • Barbara Frigerio,
  • Elisa Corsiero,
  • Francesco Raspagliesi,
  • Sophia N. Karagiannis,
  • Silvana Canevari,
  • Delia Mezzanzanica,
  • Mariangela Figini

摘要

Folate receptor alpha (FRα), a membrane protein involved in folate transport, is a promising therapeutic target for ovarian cancer and other malignancies. The murine Monoclonal antibody (MAb) MOv19, developed in our lab, has pioneered the development of chimeric antibody-drug conjugates currently approved or in clinical trials for the treatment of FRα-positive cancers. To further reduce antibody’s immunogenicity, we engineered and characterized a new fully human IgG1 antibody (AFRA hIgG1) to FRα starting from MOv19. AFRA hIgG1 was constructed and characterized for binding affinity, specificity to purified FRα and various FRα-expressing tumor cells and ability to recruit effector cells in vitro in comparison to the chimeric version of MOv19 (ChiMOv19). AFRA hIgG1 and ChiMOv19 have comparable functional affinities being 10−9 M and 10−10 M, respectively although AFRA hIgG1 has an intrinsic constant affinity 103 lower than that of ChiMOv19, 2.6 × 10−7 M vs. 3.5 × 10−10 M, respectively. Furthermore, AFRA hIgG1 demonstrated a better binding kinetic with an overall efficacy comparable to ChiMOv19 in recruiting effector cell functions. These findings highlight that functional affinity, rather than intrinsic affinity, is a key determinant of biological response. AFRA hIgG1 shows promise as a biologic agent for the treatment of FRα-positive cancers.