Prostate stem cell antigen (PSCA), a 123-amino acid cell surface glycoprotein, is highly expressed in both local and metastatic prostate cancers as well as in a large proportion of bladder and pancreatic cancers. PSCA overexpression correlates with a high risk of recurrence after primary therapy for prostate cancer. We have reported previously that anti-PSCA monoclonal antibody (mAb) 1G8 inhibits tumor growth, prevents metastasis, and prolongs the survival of mice inoculated with human prostate cancer cell lines and xenografts. The current study was undertaken to elucidate the mechanism of action of anti-PSCA antibody therapy. In particular, we asked whether antitumor activity resulted from recruitment of an immune response or a direct effect on the tumor cell itself. In vitro assays show that both intact 1G8 and F(abV ) 2 fragments of 1G8 induce prostate cancer cell death. The anti-PSCA antibody-induced cell death is caspase independent and requires antigen cross-linking. These results were confirmed in in vivo models in which both 1G8 and F(abV ) 2 fragments were able to inhibit prostate tumor formation and growth equally. These results suggest that the anti-PSCA mAb 1G8 acts by a direct, Fc-independent mechanism to inhibit prostate tumor growth both in vitro and in vivo. (Cancer Res 2005; 65(20): 9495-500)
Electrospun nanofiber membranes having a hierarchical structure with multilevel roughness were generated via electrospinning of poly (vinylidene fluoride) (PVDF)-SiO 2 blend solutions.The composite PVDF-SiO 2 nanofiber membranes were then endowed with superhydrophobicity by the fluorosilanization of the surface with low surface energy fluoroalkylsilane (FAS). The results showed that when the SiO 2 content in the dope solutions increased from 0 wt% to 8 wt%, the water contact angles of the FAS modified nanofiber membranes increased significantly from 130.4° to 160.5°. The increment of the silica content in the dope solutions decreased the fiber diameters and pore sizes of the modified membranes, while the mechanical properties were enhanced with the silica addition. The liquid entry pressures of the membranes increased gradually from 84 kPa to 195 kPa with silica addition due to the increased contact angles and decreased pore size. Vacuum membrane distillation experiments were carried out for the modified nanofiber membranes to evaluate the anti-wetting properties. The optimal superhydrophobic nanofiber membrane maintained a stable flux of 31.5 kg/m 2 h with a permeate conductivity approximately 10 μs/cm over the entire test, while the fluxes and conductivities of the nanofiber membranes without superhydrophobicity showed a significant decrease and increase, respectively. The results indicated that the superhydrophobic modification process rendered the nanofiber membrane anti-wetting properties without compromising its excellent permeability.
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.
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