| Abstract: |
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-naï ve 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 xeno-grafted 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. Copyright © 2004 American Association for Cancer Research. |
| Keywords: |
immunohistochemistry; epidermal growth factor; controlled study; human tissue; protein expression; unclassified drug; human cell; drug efficacy; nonhuman; antineoplastic agents; bone metastasis; drug megadose; flow cytometry; lymph node metastasis; lymphatic metastasis; cell proliferation; mouse; animals; mice; gene overexpression; low drug dose; neoplasm proteins; animal experiment; animal model; membrane proteins; tumor xenograft; transfection; tumor antigen; time factors; prostate cancer; prostatic neoplasms; cloning, molecular; cancer inhibition; antibodies, monoclonal; prostate; disease severity; amino acid sequence; molecular sequence data; sequence homology, amino acid; kinetics; recombinant fusion proteins; tissue distribution; brain; rna, messenger; oligonucleotide array sequence analysis; nucleotide sequence; cell membrane; neoplasm metastasis; microscopy, fluorescence; protein structure, tertiary; cathepsin b; cross reaction; surface plasmon resonance; oligopeptides; combined immunodeficiency; drug conjugation; hormone resistance; valine; plasma protein; dna, complementary; antibody conjugate; hybridomas; citrulline; humans; human; male; priority journal; article; auristatin e monoclonal antibody pr1 conjugate; follistatin; tomoregulin
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