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) |