Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer

Mol Cancer Ther. 2004 Aug;3(8):921-32.


Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor-like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B-sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use*
  • Brain / metabolism
  • Cell Membrane / metabolism
  • Cell Proliferation
  • Cloning, Molecular
  • DNA, Complementary / metabolism
  • Flow Cytometry
  • Follistatin / chemistry
  • Humans
  • Hybridomas / chemistry
  • Immunohistochemistry
  • Kinetics
  • Lymphatic Metastasis
  • Male
  • Membrane Proteins / chemistry*
  • Membrane Proteins / immunology*
  • Mice
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Neoplasm Metastasis
  • Neoplasm Proteins / chemistry*
  • Neoplasm Proteins / immunology*
  • Oligonucleotide Array Sequence Analysis
  • Oligopeptides / chemistry
  • Oligopeptides / therapeutic use*
  • Prostate / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Protein Structure, Tertiary
  • RNA, Messenger / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Surface Plasmon Resonance
  • Time Factors
  • Transfection


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • DNA, Complementary
  • Follistatin
  • Membrane Proteins
  • Neoplasm Proteins
  • Oligopeptides
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • TMEFF2 protein, human
  • soblidotin