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
リソース情報
ヒト・動物細胞 J#176-3.2(RCB1918)