論文 - 詳細
| RRC ID | 68911 |
|---|---|
| 著者 | Ukaji T, Takemoto A, Shibata H, Kakino M, Takagi S, Katayama R, Fujita N. |
| タイトル | Novel knock-in mouse model for the evaluation of the therapeutic efficacy and toxicity of human podoplanin-targeting agents. |
| ジャーナル | Cancer Sci |
| Abstract |
Podoplanin is a key molecule for enhancing tumor-induced platelet aggregation. Podoplanin interacts with CLEC-2 on platelets via PLatelet Aggregation-inducing domains (PLAGs). Among our generated antibodies, those targeting the fourth PLAG domain (PLAG4) strongly suppress podoplanin-CLEC-2 binding and podoplanin-expressing tumor growth and metastasis. We previously performed a single-dose toxicity study of PLAG4-targeting anti-podoplanin-neutralizing antibodies and found no acute toxicity in cynomolgus monkeys. To confirm the therapeutic efficacy and toxicity of podoplanin-targeting antibodies, a syngeneic mouse model that enables repeated dose toxicity tests is needed. Replacement of mouse PLAG1-PLAG4 domains with human homologous domains drastically decreased the platelet-aggregating activity. Therefore, we searched the critical domain of the platelet-aggregating activity in mouse podoplanin and found that the mouse PLAG4 domain played a critical role in platelet aggregation, similar to the human PLAG4 domain. Human/mouse chimeric podoplanin, in which a limited region containing mouse PLAG4 was replaced with human homologous region, exhibited a similar platelet-aggregating activity to wild-type mouse podoplanin. Thus, we generated knock-in mice with human/mouse chimeric podoplanin expression (PdpnKI/KI mice). Our previously established PLAG4-targeting antibodies could suppress human/mouse chimeric podoplanin-mediated platelet aggregation and tumor growth in PdpnKI/KI mice. Repeated treatment of PdpnKI/KI mice with antibody-dependent cell-mediated cytotoxicity activity-possessing PG4D2 antibody did not result in toxicity or changes in hematological and biochemical parameters. Our results suggest that anti-podoplanin-neutralizing antibodies could be used safely as novel anti-tumor agents. Our generated PdpnKI/KI mice are useful for investigating the efficacy and toxicity of human podoplanin-targeting drugs. |
| 巻・号 | 112(6) |
| ページ | 2299-2313 |
| 公開日 | 2021-6-1 |
| DOI | 10.1111/cas.14891 |
| PMID | 33735501 |
| PMC | PMC8177788 |
| MeSH | Animals Antibodies, Monoclonal / pharmacology Antibodies, Monoclonal / therapeutic use* Antibodies, Neutralizing / pharmacology Antibodies, Neutralizing / therapeutic use* Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use* Cell Line, Tumor Humans Membrane Glycoproteins / chemistry Membrane Glycoproteins / genetics Membrane Glycoproteins / immunology Membrane Glycoproteins / metabolism* Mice Mice, Inbred C57BL Mice, Transgenic Platelet Activation / drug effects Platelet Aggregation / drug effects Protein Domains Recombinant Fusion Proteins / chemistry Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / metabolism Xenograft Model Antitumor Assays |
| IF | 4.966 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | J#176-3.2(RCB1918) |