Glypican-3-Targeted Alpha Particle Therapy for Hepatocellular Carcinoma.
Glypican-3-Targeted Alpha Particle Therapy for Hepatocellular Carcinoma.
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DOI：
10.3390/molecules26010004
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发表时间：
2020-12-22
期刊：
影响因子：
--
通讯作者：
Escorcia FE
中科院分区：
文献类型：
--
作者：
Bell MM;Gutsche NT;King AP;Baidoo KE;Kelada OJ;Choyke PL;Escorcia FE
磷脂酰肌醇蛋白聚糖-3（GPC-3）在75%的肝细胞癌（HCC）中表达，但在正常肝脏中不表达，使其成为有希望的HCC治疗靶点。GC 33是一种特异于GPC 3的全长人源化单克隆IgG 1，可在体内定位于HCC。在HCC患者中评价时，单独使用GC 33未能证明治疗效果;然而，我们认为，用治疗性放射性核素对抗体进行细胞毒性功能化可能是必要的。由放射性同位素如Actinium-225（Ac-225）发射的α粒子表现出高线性能量转移和短路径长度，当靶向肿瘤时，可以有效地杀死癌症并限制旁观者细胞毒性。Macropa是一种18元杂环冠醚，在室温下能稳定地螯合Ac-225。在这里，我们合成并评估了[225 Ac]Ac-Macropa-GC 33在移植有表达GPC 3的人肝癌细胞系HepG 2的小鼠中的功效。在初步剂量探索研究后，用（1）PBS、（2）质量当量的未修饰GC 33、（3）18.5 kBq [225 Ac]Ac-Macropa-IgG 1（同种型对照）、（4）9.25 kBq [225 Ac] Ac-Macropa-GC 33和（5）18.5 kBq [225 Ac]Ac-Macropa-GC 33处理小鼠（每组n = 10）。虽然在接受放射性缀合物的所有组中观察到显著的毒性，但与PBS（p = 0.0012）和18.5 kBq [225 Ac] Ac-IgG 1（p = 0.0412）相比，9.25 kBq [225 Ac]Ac-Macropa-GC 33组表现出适度的存活优势。血液学分析表明，与PBS和未修饰的GC 33对照组相比，所有放射缀合物处理组中的白色血细胞显著快速减少。我们的研究强调了使用血液循环时间长的直接标记生物分子用于达特的显著缺点。减轻这种治疗毒性的策略包括剂量分级、预靶向和使用较小的靶向配体。
Glypican-3 (GPC3) is expressed in 75% of hepatocellular carcinoma (HCC), but not normal liver, making it a promising HCC therapeutic target. GC33 is a full-length humanized monoclonal IgG1 specific to GPC3 that can localize to HCC in vivo. GC33 alone failed to demonstrate therapeutic efficacy when evaluated in patients with HCC; however, we posit that cytotoxic functionalization of the antibody with therapeutic radionuclides, may be warranted. Alpha particles, which are emitted by radioisotopes such as Actinium-225 (Ac-225) exhibit high linear energy transfer and short pathlength that, when targeted to tumors, can effectively kill cancer and limit bystander cytotoxicity. Macropa, an 18-member heterocyclic crown ether, can stably chelate Ac-225 at room temperature. Here, we synthesized and evaluated the efficacy of [225Ac]Ac–Macropa–GC33 in mice engrafted with the GPC3-expressing human liver cancer cell line HepG2. Following a pilot dose-finding study, mice (n = 10 per group) were treated with (1) PBS, (2) mass-equivalent unmodified GC33, (3) 18.5 kBq [225Ac]Ac–Macropa–IgG1 (isotype control), (4) 9.25 kBq [225Ac]Ac–Macropa–GC33, and (5) 18.5 kBq [225Ac]Ac–Macropa–GC33. While significant toxicity was observed in all groups receiving radioconjugates, the 9.25 kBq [225Ac]Ac–Macropa–GC33 group demonstrated a modest survival advantage compared to PBS (p = 0.0012) and 18.5 kBq [225Ac]Ac–IgG1 (p = 0.0412). Hematological analysis demonstrated a marked, rapid reduction in white blood cells in all radioconjugate-treated groups compared to the PBS and unmodified GC33 control groups. Our studies highlight a significant disadvantage of using directly-labeled biomolecules with long blood circulation times for TAT. Strategies to mitigate such treatment toxicity include dose fractionation, pretargeting, and using smaller targeting ligands.
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影响因子：
11.2
作者：
Ishiguro, Takahiro;Sugimoto, Masamichi;Yamada-Okabe, Hisafumi
通讯作者：
Yamada-Okabe, Hisafumi
影响因子：
81.5
作者：
Llovet, Josep M.;Zucman-Rossi, Jessica;Gores, Gregory
通讯作者：
Gores, Gregory
影响因子：
25.7
作者：
Abou-Alfa, Ghassan K.;Puig, Oscar;Yen, Chia-Jui
通讯作者：
Yen, Chia-Jui
影响因子：
5.2
作者：
Shirakawa, Hirofumi;Kuronuma, Toshimitsu;Nakatsura, Tetsuya
通讯作者：
Nakatsura, Tetsuya
影响因子：
11.2
作者：
Sharma SK;Chow A;Monette S;Vivier D;Pourat J;Edwards KJ;Dilling TR;Abdel-Atti D;Zeglis BM;Poirier JT;Lewis JS
通讯作者：
Lewis JS