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Targeting, Imaging, and Therapy Using a Humanized Antiprostate Stem Cell Antigen (PSCA) Antibody

Olafsen, Tove*; Gu, Zhennan; Sherman, Mark A.; Leyton, Jeffrey V.*; Witkosky, Michael E.; Shively, John E.§; Raubitschek, Andrew A.; Morrison, Sherie L.; Wu, Anna M.*; Reiter, Robert E.

doi: 10.1097/CJI.0b013e318031b53b
Basic Studies

The murine 1G8 (mu1G8) monoclonal antibody directed against prostate stem cell antigen (PSCA) prevents prostate tumor establishment, growth, and metastasis in murine models. To further delineate in vivo targeting properties, mu1G8 was radiolabeled with In-111 and evaluated in nude mice bearing PC3-PSCA xenografts. Tumor activity ranged from 11.8% to 17.1% injected dose per gram (ID/g) at 24 to 96 hours postinjection. To extend the clinical applicability of mu1G8, a chimeric 1G8 antibody was produced that exhibited specific binding to PSCA and significant antitumor effect over mu1G8 in established LAPC-9 prostate cancer xenografts (P=0.0014). However, low expression yields and instability prompted us to humanize 1G8 by grafting the complementary determining regions onto the stable, human Fv framework of anti-p185HER2 4D5v8 (trastuzumab). Two humanized 1G8 (hu1G8) versions (A and B) that differed in the number of murine residues present in the C-terminal half of CDR-H2, were produced. Biacore binding studies demonstrated affinities of 1.47 nM for mu1G8 and 3.74 nM for hu2B3-B, representing a 2.5-fold reduction. Tumor targeting of version B radioiodinated with 124I was evaluated by serial microPET imaging. Specific tumor targeting of 124I-hu1G8-B to PC3-PSCA [12.7 (±1.6)% ID/g at 94 h] and LAPC-9 [6.6 (±0.9)% ID/g at 168 h) xenografts was observed. Inhibition of tumor growth by hu1G8-B was demonstrated in mice bearing low-expressing SW-780-PSCA bladder carcinoma xenografts. In this model, the mu1G8 was ineffective, whereas the hu1G8-B exhibited approximately 50% inhibitory effect. These data support further development of hu1G8 anti-PSCA antibody for targeted imaging and therapy for tumors of urogenital origin.

*Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging

Department of Urology, David Geffen School of Medicine at University of California, Los Angeles

Divisions of ‡Information Sciences

§Immunology, Beckman Research Institute of the City of Hope

Department of Radioimmunotherapy, City of Hope National Medical Center, Duarte

Department of Microbiology, Immunology and Molecular Genetics and Molecular Biology Institute, University of California, Los Angeles, CA

Supported by NIH Specialized Program of Research Excellence (SPORE) in Prostate Cancer P50 CA 92131 and P01 CA 43904. John E. Shivley and Andrew A. Raubitschek are members of the City of Hope Comprehensive Cancer Center (CA 33572). Sherie L. Morrison, Anna M. Wu, and Robert E. Reiter are members of the UCLA Jonsson Comprehensive Cancer Center (CA 16042).

Tove Olafsen and Zhennan Gu contributed equally to this work.

Financial Disclosure: The authors have declared there are no financial conflicts of interest related to this work.

Reprints: Tove Olafsen, Crump Institute for Molecular Imaging, David Geffen School of Medicine, UCLA, 700 Westwood Plaza, Los Angeles, CA 90095 (e-mail: tolafsen@mednet.ucla.edu).

Received for publication June 30, 2006; accepted October 25, 2006

© 2007 Lippincott Williams & Wilkins, Inc.