Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer
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-naive 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.
|Authors||Afar, D. E.;Bhaskar, V.;Ibsen, E.;Breinberg, D.;Henshall, S. M.;Kench, J. G.;Drobnjak, M.;Powers, R.;Wong, M.;Evangelista, F.;O'Hara, C.;Powers, D.;DuBridge, R. B.;Caras, I.;Winter, R.;Anderson, T.;Solvason, N.;Stricker, P. D.;Cordon-Cardo, C.;Scher, H. I.;Grygiel, J. J.;Sutherland, R. L.;Murray, R.;Ramakrishnan, V.;Law, D. A. :|
|Publisher Name||MOLECULAR CANCER THERAPEUTICS|
|Published Date||2004-01-01 00:00:00|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15299075|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/1749|