A safety study of newly generated anti-podoplanin-neutralizing antibody in cynomolgus monkey (<i>Macaca fascicularis</i>)

Ukaji, Takao; Takemoto, Ai; Katayama, Ryohei; Takeuchi, Kengo; Fujita, Naoya

doi:10.18632/oncotarget.26055

Cited by 9 publications

(18 citation statements)

References 48 publications

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“…5,23 Among our identified PLAG domains, the fourth PLAG domain (PLAG4) in human PDPN (hPDPN) was found to play an important role in CLEC-2 binding and platelet aggregation. 23,28 The amino acid sequence alignment in mouse and human revealed that mouse PDPN (mPDPN) had a similar consensus motif (82-EELST-86) to human PLAG4 (81-EDLPT-85; Figure 1A, see Supplemental materials and methods). To evaluate the contributions of each mouse PLAG domain to CLEC-2 binding, we established CHO cells expressing PLAG domain-deleted mPDPN mutants (CHO/mPDPN-ΔPLAG1, -ΔPLAG3, -ΔPLAG4, -ΔPLAG1+4, -ΔPLAG3+4, and -ΔPLAG1+3+4; Figure 1B) and assessed their binding abilities to recombinant mouse CLEC-2 (mCLEC-2).…”

Section: Critical Role Of the Mouse Plag4 Domain In Clec-2 Binding And Platelet Activationmentioning

confidence: 99%

“…Each sample was treated with a previously described procedure. 28 Samples were incubated with primary antibodies to PDPN (mouse anti-human PDPN mAbs, PG4D1 and PG4D2; Syrian hamster anti-mouse PDPN mAb, ab11936, Abcam) and β-actin (clone, AC-15; Sigma-Aldrich), treated with HRP-conjugated anti-mouse IgG (RPN2232, GE Healthcare), anti-hamster IgG (57003, Cappel), and mouse TrueBlot ULTRA (18-8817-33, Rockland), and then reacted with an ECL Prime Western Blotting Detection reagent (GE Healthcare). The proteins were visualized with enhanced chemiluminescence using Amersham Imager 600 (GE Healthcare).…”

Section: Western Blot Analysismentioning

confidence: 99%

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Novel knock‐in mouse model for the evaluation of the therapeutic efficacy and toxicity of human podoplanin–targeting agents

Ukaji¹,

Takemoto²,

Shibata

et al. 2021

Cancer Science

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Section: Critical Role Of the Mouse Plag4 Domain In Clec-2 Binding And Platelet Activationmentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

Novel knock‐in mouse model for the evaluation of the therapeutic efficacy and toxicity of human podoplanin–targeting agents

Ukaji¹,

Takemoto²,

Shibata

et al. 2021

Cancer Science

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“…In addition to OSCC, PDPN promotes a variety of other cancers including mammary carcinoma [ 62 , 63 ], glioma [ 64 – 67 ], melanoma [ 59 , 68 , 69 ], ovarian cancer [ 70 ], and pulmonary adenocarcinoma [ 71 – 73 ]. Indeed, PDPN has been identified as an enticing target for chemotherapy [ 74 , 75 ]. The roles of cadherins and PDPN in contact normalization described in this study should yield insight into fundamental mechanisms that affect the general process of cancer development and progression at the cellular level of the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Heterocellular N-cadherin junctions enable nontransformed cells to inhibit the growth of adjacent transformed cells

et al. 2022

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Background The Src tyrosine kinase phosphorylates effector proteins to induce expression of the podoplanin (PDPN) receptor in order to promote tumor progression. However, nontransformed cells can normalize the growth and morphology of neighboring transformed cells. Transformed cells must escape this process, called “contact normalization”, to become invasive and malignant. Contact normalization requires junctional communication between transformed and nontransformed cells. However, specific junctions that mediate this process have not been defined. This study aimed to identify junctional proteins required for contact normalization. Methods Src transformed cells and oral squamous cell carcinoma cells were cultured with nontransformed cells. Formation of heterocellular adherens junctions between transformed and nontransformed cells was visualized by fluorescent microscopy. CRISPR technology was used to produce cadherin deficient and cadherin competent nontransformed cells to determine the requirement for adherens junctions during contact normalization. Contact normalization of transformed cells cultured with cadherin deficient or cadherin competent nontransformed cells was analyzed by growth assays, immunofluorescence, western blotting, and RNA-seq. In addition, Src transformed cells expressing PDPN under a constitutively active exogenous promoter were used to examine the ability of PDPN to override contact normalization. Results We found that N-cadherin (N-Cdh) appeared to mediate contact normalization. Cadherin competent cells that expressed N-Cdh inhibited the growth of neighboring transformed cells in culture, while cadherin deficient cells failed to inhibit the growth of these cells. Results from RNA-seq analysis indicate that about 10% of the transcripts affected by contact normalization relied on cadherin mediated communication, and this set of genes includes PDPN. In contrast, cadherin deficient cells failed to inhibit PDPN expression or normalize the growth of adjacent transformed cells. These data indicate that nontransformed cells formed heterocellular cadherin junctions to inhibit PDPN expression in adjacent transformed cells. Moreover, we found that PDPN enabled transformed cells to override the effects of contact normalization in the face of continued N-Cdh expression. Cadherin competent cells failed to normalize the growth of transformed cells expressing PDPN under a constitutively active exogenous promoter. Conclusions Nontransformed cells form cadherin junctions with adjacent transformed cells to decrease PDPN expression in order to inhibit tumor cell proliferation. Plain English Summary Cancer begins when a single cell acquires changes that enables them to form tumors. During these beginning stages of cancer development, normal cells surround and directly contact the cancer cell to prevent tumor formation and inhibit cancer progression. This process is called contact normalization. Cancer cells must break free from contact normalization to progress into a malignant cancer. Contact normalization is a widespread and powerful process; however, not much is known about the mechanisms involved in this process. This work identifies proteins required to form contacts between normal cells and cancer cells, and explores pathways by which cancer cells override contact normalization to progress into malignant cancers. Graphical abstract

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“…Anti-human PDPN mAb NZ-1, which recognizes the PLAG2/3 domain, has a neutralizing activity in relation to the PDPN-CLEC-2 interaction and inhibits PDPN-induced platelet aggregation and hematogenous lung metastasis [16,66] (Figure 1). Other anti-PDPN mAbs, P2-0 [152] and MS-1 [153] also recognize the PLAG2/3 domain, and 2F7 [154] recognizes the PLD/PLAG4 domain. These mAbs also suppress platelet aggregation and hematogenous pulmonary metastasis by inhibiting CLEC-2 interaction.…”

Section: Anti-pdpn Monoclonal Antibodies (Mabs)mentioning

confidence: 99%

Roles of Podoplanin in Malignant Progression of Tumor

Suzuki

Kaneko

Kato

2022

Cells

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Podoplanin (PDPN) is a cell-surface mucin-like glycoprotein that plays a critical role in tumor development and normal development of the lung, kidney, and lymphatic vascular systems. PDPN is overexpressed in several tumors and is involved in their malignancy. PDPN induces platelet aggregation through binding to platelet receptor C-type lectin-like receptor 2. Furthermore, PDPN modulates signal transductions that regulate cell proliferation, differentiation, migration, invasion, epithelial-to-mesenchymal transition, and stemness, all of which are crucial for the malignant progression of tumor. In the tumor microenvironment (TME), PDPN expression is upregulated in the tumor stroma, including cancer-associated fibroblasts (CAFs) and immune cells. CAFs play significant roles in the extracellular matrix remodeling and the development of immunosuppressive TME. Additionally, PDPN functions as a co-inhibitory molecule on T cells, indicating its involvement with immune evasion. In this review, we describe the mechanistic basis and diverse roles of PDPN in the malignant progression of tumors and discuss the possibility of the clinical application of PDPN-targeted cancer therapy, including cancer-specific monoclonal antibodies, and chimeric antigen receptor T technologies.

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A safety study of newly generated anti-podoplanin-neutralizing antibody in cynomolgus monkey (Macaca fascicularis)

Cited by 9 publications

References 48 publications

Novel knock‐in mouse model for the evaluation of the therapeutic efficacy and toxicity of human podoplanin–targeting agents

Novel knock‐in mouse model for the evaluation of the therapeutic efficacy and toxicity of human podoplanin–targeting agents

Heterocellular N-cadherin junctions enable nontransformed cells to inhibit the growth of adjacent transformed cells

Roles of Podoplanin in Malignant Progression of Tumor

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