This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Afar, D. E.H. Articles by Law, D. A. Search for Related Content PubMed PubMed Citation Articles by Afar, D. E.H. Articles by Law, D. A.

¹ Protein Design Labs, Inc., Fremont, California; ² Garvan Institute of Medical Research and Departments of ³ Urology and ⁴ Medical Oncology, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, Australia; ⁵ Department of Tissue Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales, Australia; ⁶ Memorial Sloan Kettering Cancer Center, New York, New York; and ⁷ Eos Biotechnology, Inc., Fremont, California

Requests for reprints: Daniel E.H. Afar, Protein Design Labs, Inc., 34801 Campus Drive, Fremont, CA 94555. Phone: 510-574-1665; Fax: 510-574-1661. E-mail: dafar{at}pdl.com

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: D.E.H. Afar and V. Bhaskar contributed equally to this work. R. Winter is currently at Raven Biotechnologies, Inc., South San Francisco, CA 94080. N. Solvasen is currently at Bayhill Therapeutics, Inc., Palo Alto, CA 94303.

Received 4/ 9/04; revised 5/24/04; accepted 6/15/04.