| RRC ID |
69866
|
| 著者 |
Takashima H, Koga Y, Manabe S, Ohnuki K, Tsumura R, Anzai T, Iwata N, Wang Y, Yokokita T, Komori Y, Mori D, Usuda S, Haba H, Fujii H, Matsumura Y, Yasunaga M.
|
| タイトル |
Radioimmunotherapy with an 211 At-labeled anti-tissue factor antibody protected by sodium ascorbate.
|
| ジャーナル |
Cancer Sci
|
| Abstract |
Tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is abundantly expressed in various cancers including gastric cancer. Anti-TF monoclonal antibodies (mAbs) capable of targeting cancers have been successfully applied to armed antibodies such as antibody-drug conjugates (ADCs) and molecular imaging probes. We prepared an anti-TF mAb, clone 1084, labeled with astatine-211 (211 At), as a promising alpha emitter for cancer treatment. Alpha particles are characterized by high linear energy transfer and a range of 50-100 µm in tissue. Therefore, selective and efficient tumor accumulation of alpha emitters results in potent antitumor activities against cancer cells with minor effects on normal cells adjacent to the tumor. Although the 211 At-conjugated clone 1084 (211 At-anti-TF mAb) was disrupted by an 211 At-induced radiochemical reaction, we demonstrated that astatinated anti-TF mAbs eluted in 0.6% or 1.2% sodium ascorbate (SA) solution were protected from antibody denaturation, which contributed to the maintenance of cellular binding activities and cytocidal effects of this immunoconjugate. Although body weight loss was observed in mice administered a 1.2% SA solution, the loss was transient and the radioprotectant seemed to be tolerable in vivo. In a high TF-expressing gastric cancer xenograft model, 211 At-anti-TF mAb in 1.2% SA exerted a significantly greater antitumor effect than nonprotected 211 At-anti-TF mAb. Moreover, the antitumor activities of the protected immunoconjugate in gastric cancer xenograft models were dependent on the level of TF in cancer cells. These findings suggest the clinical availability of the radioprotectant and applicability of clone 1084 to 211 At-radioimmunotherapy.
|
| 巻・号 |
112(5)
|
| ページ |
1975-1986
|
| 公開日 |
2021-5-1
|
| DOI |
10.1111/cas.14857
|
| PMID |
33606344
|
| PMC |
PMC8088967
|
| MeSH |
Animals
Antibodies, Monoclonal, Humanized / pharmacokinetics
Antibodies, Monoclonal, Humanized / therapeutic use*
Ascorbic Acid / therapeutic use*
Astatine / pharmacokinetics
Astatine / therapeutic use*
Blood Coagulation / physiology
Body Weight
Cell Line, Tumor
Female
Heterografts
Humans
Immunoconjugates / chemistry
Immunoconjugates / pharmacokinetics
Immunoconjugates / therapeutic use*
Linear Energy Transfer
Mice
Mice, Inbred BALB C
Mice, Nude
Protein Denaturation
Radiation-Protective Agents / therapeutic use
Radioimmunotherapy / methods*
Receptor, ErbB-2 / antagonists & inhibitors
Receptor, ErbB-2 / metabolism
Stomach Neoplasms / metabolism
Stomach Neoplasms / pathology
Stomach Neoplasms / therapy*
Thromboplastin / immunology*
Thromboplastin / metabolism
|
| IF |
4.966
|
| リソース情報 |
| ヒト・動物細胞 |
SH-10-TC(RCB1940) |
