Human Antibody VH Domains Targeting GPNMB and VCAM-1 as Candidate Therapeutics for Cancers

Mol Pharm. 2023 May 1;20(5):2754-2760. doi: 10.1021/acs.molpharmaceut.3c00173. Epub 2023 Apr 17.

Abstract

The elevated expression of GPNMB and VCAM-1 has been observed in many cancers including breast cancer, melanoma, and prostate cancers. Such overexpression of GPNMB and VCAM-1 has been associated with poor prognosis and increased cancer metastasis. Thus, GPNMB and VCAM-1 are potential targets for immunotherapies across multiple cancers. In this study, two high-affinity specific human VH domain antibody candidates, 87 (GPNMB) and 1B2 (VCAM-1), were isolated from our in-house proprietary phage-displayed human VH antibody domain libraries. The avidity was increased after conversion to VH-Fc. Domain-based bispecific T-cell engagers (DbTE) based on these two antibodies combined with the anti-CD3ε OKT3 antibody exhibited potent killing against GPNMB and VCAM-1-positive cancer cells, respectively. Hence, these two domain antibodies are promising therapeutic candidates for cancers expressing GPNMB or VCAM-1.

Keywords: DbTE (Domain based bispecific T cell engager); VH domain; human GPNMB (DC-HIL, Osteoactivin); human VCAM-1; therapeutic antibody.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies
  • Breast Neoplasms* / drug therapy
  • Female
  • Humans
  • Immunoglobulin Variable Region
  • Melanoma*
  • Membrane Glycoproteins
  • Transcription Factors
  • Vascular Cell Adhesion Molecule-1

Substances

  • Vascular Cell Adhesion Molecule-1
  • Antibodies
  • Immunoglobulin Variable Region
  • Transcription Factors
  • GPNMB protein, human
  • Membrane Glycoproteins