An Anti-Nucleic Acid Antibody Delivers Antigen to the Cross-Presentation Pathway in Dendritic Cells and Potentiates Therapeutic Antitumor Effects

Pham, Dinh‐Chuong; Woo, Min-Yeong; Kim, Yong‐Sung; Park, Sun; Kwon, Myung-Hee

doi:10.4049/jimmunol.1200804

Cited by 7 publications

(4 citation statements)

References 47 publications

(69 reference statements)

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“…We reported previously the results of a mutational analysis based on the x-ray crystallographic structure of 3D8 scFv, which showed that the His residues in CDR1 of the heavy chain (HCDR1) and CDR3 of the light chain (LCDR3) are critical for DNA hydrolysis ( 15 ). 3D8 scFv is endocytosed via the caveolae-mediated pathway and localizes to the cytosol without translocating to the nucleus ( 14 , 16 ). Moreover, we found that the activities of 3D8 scFv are relatively tolerant of alteration of the CDR.…”

Section: Introductionmentioning

confidence: 99%

Functional Consequences of Complementarity-determining Region Deactivation in a Multifunctional Anti-nucleic Acid Antibody

Kim

Roh

Seo

et al. 2013

Journal of Biological Chemistry

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Background: A subset of anti-DNA antibodies have DNA-hydrolysis and/or cell-penetration activity.Results: Deactivation of different complementarity-determining regions (CDRs) in a multifunctional anti-nucleic acid antibody alters the properties of the antibody.Conclusion: CDR1 of the light chain plays a crucial role in maintaining the properties of 3D8 scFv.Significance: Single complete CDR deactivation allows exploration of the molecular features of multifunctional anti-DNA antibodies.

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Section: Introductionmentioning

confidence: 99%

Functional Consequences of Complementarity-determining Region Deactivation in a Multifunctional Anti-nucleic Acid Antibody

Kim

Roh

Seo

et al. 2013

Journal of Biological Chemistry

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“…Confocal microscopy revealed that all internalizable 3D8 antibodies localized to the cytosol of THP-1 cells (Figure 2C ). Previous studies report internalization of 3D8 scFv into the cytosol of human epithelial (HeLa) cells, human embryonic kidney (HEK293T) cells ( 19 , 21 ), and mouse dendritic (DC2.4) cells ( 22 ). By contrast, a negative control polyclonal human IgG localized to the cell surface [probably due to capture by Fcγ receptors (FcγRs)].…”

Section: Resultsmentioning

confidence: 99%

Cytosolic Internalization of Anti-DNA Antibodies by Human Monocytes Induces Production of Pro-inflammatory Cytokines Independently of the Tripartite Motif-Containing 21 (TRIM21)-Mediated Pathway

et al. 2018

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Anti-DNA autoantibodies are a hallmark of systemic lupus erythematosus (SLE). A subset of anti-DNA IgG autoantibodies is cell-internalizable; thus they can enter living cells in the form of free IgG. However, the contribution made by the Fc region of internalized free-form IgG to the cytokine response has not been studied, despite the recent discovery of tripartite motif-containing 21 (TRIM21), a cytosolic Fc receptor involved in immune signaling. This study used an internalizable IgG anti-DNA antibody (3D8) to examine the cytokine responses of human monocytes to the Fc region of cytosolic free IgG. Internalization of 3D8 IgG and a 3D8 single-chain variable fragment-Fc (scFv-Fc) induced production of IL-8 and TNF-α via activation of NF-κB. By contrast, a 3D8 scFv (comprising variable domains alone) did not. This suggests Fc-dependent cytokine signaling. A 3D8 IgG-N434D mutant that is not recognized by TRIM21 induced greater production of cytokines than 3D8 IgG. Moreover the amounts of cytokines induced by 3D8 IgG in TRIM21-knockdown THP-1 cells were higher than those in control cells, indicating that cytokine signaling is not mediated by TRIM21. The results suggest the existence of a novel Fc-dependent signaling pathway that is activated upon internalization of IgG antibodies by human monocytes.

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“… 19 Antibodies coupled to tumour proteins have been shown to induce CD8 + T cell activation via cross presentation of antibody complexes by mouse DCs. 20 In addition, a cancer vaccine based on coupling tumour antigens such as her-2/neu to an scFv anti-CD19 mAb has been shown to reduce tumour growth. 21 …”

Section: Discussionmentioning

confidence: 99%

MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4 ⁺ T cells in vivo

Guy,

Terry,

McGuire

et al. 2023

OncoImmunology

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There has been growing interest in the role of B cells in antitumour immunity and potential use in adoptive cellular therapies. To date, the success of such therapies is limited. The intrinsic capacity of B cells to specifically activate tumour-specific CD4+ T cells in vivo via TCR-dependent interactions remains poorly defined. We have developed an in vivo tumour model that utilizes MHCII I-E restriction which limits antigen presentation to tumour-specific CD4 T cells to either tumour-specific B cells or host myeloid antigen presenting cells (APCs) in lymphopenic RAG-/-mice. We have previously shown that these naive tumour-specific CD4+ T cells can successfully eradicate established tumours in this model when activated by host APCs. When naïve tumour-specific B cells are the only source of I-E+ APC, very limited proliferation of naïve CD4+ T cells is observed, whereas host I-E+ APCs are potent T cell activators. B cells pre-activated with an anti-CD40 agonistic antibody in vivo support increased T cell proliferation, although far less than host APCs. CD4+ T cells that have already differentiated to an effector/central memory phenotype proliferate more readily in response to naïve B cells, although still 100-fold less than in response to host APCs. This study demonstrates that even in a significantly lymphopenic environment, myeloid APCs are the dominant primary activators of tumour-specific T cells, in contrast to the very limited capacity of tumour-specific B cells. This suggests that future anti-tumour therapies that incorporate activated B cells should also include mechanisms that activate host APCs.

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An Anti-Nucleic Acid Antibody Delivers Antigen to the Cross-Presentation Pathway in Dendritic Cells and Potentiates Therapeutic Antitumor Effects

Cited by 7 publications

References 47 publications

Functional Consequences of Complementarity-determining Region Deactivation in a Multifunctional Anti-nucleic Acid Antibody

Functional Consequences of Complementarity-determining Region Deactivation in a Multifunctional Anti-nucleic Acid Antibody

Cytosolic Internalization of Anti-DNA Antibodies by Human Monocytes Induces Production of Pro-inflammatory Cytokines Independently of the Tripartite Motif-Containing 21 (TRIM21)-Mediated Pathway

MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4 ⁺ T cells in vivo

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An Anti-Nucleic Acid Antibody Delivers Antigen to the Cross-Presentation Pathway in Dendritic Cells and Potentiates Therapeutic Antitumor Effects

Cited by 7 publications

References 47 publications

Functional Consequences of Complementarity-determining Region Deactivation in a Multifunctional Anti-nucleic Acid Antibody

Functional Consequences of Complementarity-determining Region Deactivation in a Multifunctional Anti-nucleic Acid Antibody

Cytosolic Internalization of Anti-DNA Antibodies by Human Monocytes Induces Production of Pro-inflammatory Cytokines Independently of the Tripartite Motif-Containing 21 (TRIM21)-Mediated Pathway

MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4 + T cells in vivo

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MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4 ⁺ T cells in vivo