Tolerogenic Immunotherapy: Targeting DC Surface Receptors to Induce Antigen-Specific Tolerance

Dendritic cells (DCs) are well-established as major players in the regulation of immune responses. They either induce inflammatory or tolerogenic responses, depending on the DC-subtype and stimuli they receive from the local environment. This dual capacity of DCs has raised therapeutic interest for their use to modify immune-activation via the generation of tolerogenic DCs (tolDCs). Several compounds such as vitamin D3, retinoic acid, dexamethasone, or IL-10 and TGF-β have shown potency in the induction of tolDCs. However, an increasing interest exists in defining tolerance inducing receptors on DCs for new targeting strategies aimed to develop tolerance inducing immunotherapies, on which we focus particular in this review. Ligation of specific cell surface molecules on DCs can result in antigen presentation to T cells in the presence of inhibitory costimulatory molecules and tolerogenic cytokines, giving rise to regulatory T cells. The combination of factors such as antigen structure and conformation, delivery method, and receptor specificity is of paramount importance. During the last decades, research provided many tools that can specifically target various receptors on DCs to induce a tolerogenic phenotype. Based on advances in the knowledge of pathogen recognition receptor expression profiles in human DC subsets, the most promising cell surface receptors that are currently being explored as possible targets for the induction of tolerance in DCs will be discussed. We also review the different strategies that are being tested to target DC receptors such as antigen-carbohydrate conjugates, antibody-antigen fusion proteins and antigen-adjuvant conjugates.

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Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man.

Journal of Clinical Investigation ◽

10.1172/jci110896 ◽

1983 ◽

Vol 71 (5) ◽

pp. 1431-1441 ◽

Cited By ~ 144

Author(s):

F Krempler ◽

G M Kostner ◽

A Roscher ◽

F Haslauer ◽

K Bolzano ◽

...

Keyword(s):

Cell Surface ◽

Cell Surface Receptors ◽

Specific Cell ◽

Lipoprotein A ◽

Surface Receptors ◽

Specific Cell Surface

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Identification of New Multiple Myeloma-Specific Cell Surface Antigens As Immunotherapeutic Targets

Blood ◽

10.1182/blood.v128.22.3252.3252 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3252-3252

Author(s):

Naoki Hosen ◽

Kana Hasegawa ◽

Yasutaka Aoyama ◽

Hiroyoshi Ichihara ◽

Atsuko Mugitani ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Cell Surface ◽

Surface Antigens ◽

Expression Cloning ◽

Specific Cell ◽

Cell Surface Antigens ◽

Car T Cells ◽

Car T ◽

Specific Cell Surface

Abstract Cancer-specific cell surface antigens are ideal targets for therapies using monoclonal antibodies (mAbs) and their derivatives, such as chimeric antigen receptor (CAR)-T cells. However, such antigens are not likely to remain unidentified following extensive searching by transcriptome or proteome analyses. However, we hypothesized that cancer-specific antigens formed by post-translational events, such as glycosylation, complex formation, or conformational changes, might have been missed in previous screens. Such antigens could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens recognized by these mAbs. To test our hypothesis, we applied this strategy to identify novel therapeutic targets specific for multiple myeloma (MM), a major hematological cancer. We first identified two MM-specific mAbs designated as MMG49 or R8H283 after screening more than 10,000 anti-MM mAb clones. Then, we identified the antigens recognized by these mAbs by an expression cloning method. Interestingly, genes identified as antigens for both mAbs were not specific to MM cells, suggesting that both mAbs recognize MM-specific epitopes formed by post-translational events. Finally, we showed that these mAbs or CAR-T cells derived from them could reduce tumor burden in MM-xenograft models, but did not damage normal hematopoietic cells. These results not only demonstrate that these mAb or CAR-T cell therapy is promising for MM, but also suggest that MM-specific immunotherapetic target antigens formed by post translational events may be still missed. Disclosures Aoyama: Alexion: Honoraria.

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Adeno-Associated Virus Capsids Displaying Immunoglobulin-Binding Domains Permit Antibody-Mediated Vector Retargeting to Specific Cell Surface Receptors

Journal of Virology ◽

10.1128/jvi.76.9.4559-4566.2002 ◽

2002 ◽

Vol 76 (9) ◽

pp. 4559-4566 ◽

Cited By ~ 86

Author(s):

Martin U. Ried ◽

Anne Girod ◽

Kristin Leike ◽

Hildegard Büning ◽

Michael Hallek

Keyword(s):

Cell Surface ◽

Binding Domain ◽

Cell Surface Receptors ◽

Specific Cell ◽

Broad Host Range ◽

Adeno Associated Virus ◽

Surface Receptors ◽

Vector Targeting ◽

Immunoglobulin Binding ◽

Specific Cell Surface

ABSTRACT Recombinant adeno-associated virus type 2 (rAAV2) is a promising vector for human somatic gene therapy. However, its broad host range is a disadvantage for some applications, because it reduces the specificity of the gene transfer. To overcome this limitation, we sought to create a versatile rAAV vector targeting system which would allow us to redirect rAAV binding to specific cell surface receptors by simple coupling of different ligands to its capsid. For this purpose, an immunoglobulin G (IgG) binding domain of protein A, Z34C, was inserted into the AAV2 capsid at amino acid position 587. The resulting AAV2-Z34C mutants could be packaged and purified to high titers and bound to IgG molecules. rAAV2-Z34C vectors coupled to antibodies against CD29 (β1-integrin), CD117 (c-kit receptor), and CXCR4 specifically transduced distinct human hematopoietic cell lines. In marked contrast, no transduction was seen in the absence of antibodies or in the presence of specific blocking reagents. These results demonstrate for the first time that an immunoglobulin binding domain can be inserted into the AAV2 capsid and coupled to various antibodies, which mediate the retargeting of rAAV vectors to specific cell surface receptors.

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