A HER2 Specific Nanobody-Drug Conjugate: Site-Selective Bioconjugation and In Vitro Evaluation in Breast Cancer Models

Molecules. 2025 Jan 18;30(2):391. doi: 10.3390/molecules30020391.

Abstract

A human epidermal growth factor receptor 2 (HER2)-specific nanobody called 2Rs15d, containing a His3LysHis6 segment at the C-terminus, was recombinantly produced. Subsequent site-selective acylation on the C-terminally activated lysine residue allowed installation of the cytotoxin monomethyl auristatin E-functionalized cathepsin B-sensitive payload to provide a highly homogenous nanobody-drug conjugate (NBC), which demonstrated high potency and selectivity for HER2-positive breast cancer models.

Keywords: breast cancer; nanobody; site-selective conjugation; targeted treatment.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Cathepsin B / metabolism
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunoconjugates / chemistry
  • Immunoconjugates / pharmacology
  • Oligopeptides / chemistry
  • Receptor, ErbB-2* / metabolism
  • Single-Domain Antibodies* / chemistry

Substances

  • Receptor, ErbB-2
  • Single-Domain Antibodies
  • ERBB2 protein, human
  • Cathepsin B
  • Immunoconjugates
  • monomethyl auristatin E
  • Oligopeptides
  • Antineoplastic Agents