Maruyama-Takahashi Kumiko, Shimada Naoki, Imada Teruyoshi, Maekawa-Tokuda Yoshimi, Ishii Toshihiko, Ouchi Jun, Kusaka Hideaki, Miyaji Hiromasa, Akinaga Shiro, Tanaka Akira, Shitara Kenya
Antibody Research Laboratories, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Chiyoda-ku, Tokyo, Japan.
Prostate. 2008 May 1;68(6):640-50. doi: 10.1002/pros.20728.
Fibroblast growth factor 8-isoform b (FGF8b) has been detected in human clinical sex-organ related cancers including hormone-refractory prostate cancer. There are, however, few relevant experimental models. A murine monoclonal anti-FGF8 antibody, KM1334, has been shown to neutralize FGF8b and inhibit the growth of androgen-dependent mouse mammary SC-3 cells in vitro and in vivo. In the present study, we evaluated the anti-tumor activity of KM1334 against androgen-dependent and -independent progression of FGF8b-expressing human prostate cancer xenografts.
FGF8b cDNA was transfected into androgen-dependent human prostate cancer cell line LNCaP, and its xenograft tumors were established subcutaneously in SCID mice with or without castration. KM1334 at the dose of 400 microg/head was injected twice weekly.
FGF8b-expressing LNCaP cells secreted FGF8b, showed enhanced level of Erk1/2 phosphorylation, and showed more potent growth properties than mock-expressing cells in vitro and in vivo. KM1334 reduced these properties in vitro, inhibited tumorigenecity in vivo (T/C=0.33), and showed anti-tumor activity against established tumors (T/C=0.47) of FGF8b-expressing cells. FGF8b-expressing LNCaP tumors were androgen-dependent. However, they recurred as androgen-independent FGF8b positive tumors after castration. KM1334 also inhibited the growth of established FGF8b-expressing tumors in the androgen-independent states (T/C=0.47).
These results indicate that humanized monoclonal antibodies, conserving the paratope of KM1334, are a promising candidate for therapy of FGF8b-expressing clinical prostate cancers. Follow-up studies using xenograft models with clinical FGF8b-expressing tumors are required to validate these early findings.
在包括激素难治性前列腺癌在内的人类临床性器官相关癌症中已检测到成纤维细胞生长因子8异构体b（FGF8b）。然而，相关的实验模型很少。一种鼠单克隆抗FGF8抗体KM1334已被证明能中和FGF8b并在体外和体内抑制雄激素依赖性小鼠乳腺SC-3细胞的生长。在本研究中，我们评估了KM1334对表达FGF8b的人前列腺癌异种移植瘤雄激素依赖性和非依赖性进展的抗肿瘤活性。
将FGF8b cDNA转染到雄激素依赖性人前列腺癌细胞系LNCaP中，并在有或无去势的SCID小鼠皮下建立其异种移植瘤。以400μg/只的剂量每周两次注射KM1334。
表达FGF8b的LNCaP细胞分泌FGF8b，显示出增强的Erk1/2磷酸化水平，并且在体外和体内比表达空载体的细胞具有更强的生长特性。KM1334在体外降低了这些特性，在体内抑制了肿瘤发生（T/C = 0.33），并对表达FGF8b的细胞的已建立肿瘤显示出抗肿瘤活性（T/C = 0.47）。表达FGF8b的LNCaP肿瘤是雄激素依赖性的。然而，去势后它们会复发为雄激素非依赖性FGF8b阳性肿瘤。KM1334也抑制了雄激素非依赖性状态下已建立的表达FGF8b肿瘤的生长（T/C = 0.47）。
这些结果表明，保留KM1334互补决定区的人源化单克隆抗体是治疗表达FGF8b的临床前列腺癌的有希望的候选药物。需要使用表达临床FGF8b肿瘤的异种移植模型进行后续研究来验证这些早期发现。
