Targeting, imaging, and therapy using a humanized antiprostate stem cell antigen (PSCA) antibody.
The murine 1G8 (micro1G8) 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, micro1G8 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 micro1G8, a chimeric 1G8 antibody was produced that exhibited specific binding to PSCA and significant antitumor effect over micro1G8 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-p185 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 micro1G8 and 3.74 nM for hu2B3-B, representing a 2.5-fold reduction. Tumor targeting of version B radioiodinated with I was evaluated by serial microPET imaging. Specific tumor targeting of I-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 micro1G8 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.
Olafsen
Tove
T
Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA. tolafsen@mednet.ucla.edu
Gu
Zhennan
Z
Sherman
Mark A
MA
Leyton
Jeffrey V
JV
Witkosky
Michael E
ME
Shively
John E
JE
Raubitschek
Andrew A
AA
Morrison
Sherie L
SL
Wu
Anna M
AM
Reiter
Robert E
RE
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins; D006801:Humans; D006825:Hybridomas / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000276:immunology*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017386:Sequence Homology, Amino Acid
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human