Screening of the HLDA9 panel on peripheral blood dendritic cell populations

Ding, Yitian; Ju, Xinsheng; Azlan, Maryam; Hart, Derek N.J.; Clark, Georgina J.

doi:10.1016/j.imlet.2010.10.010

Cited by 7 publications

(9 citation statements)

References 16 publications

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“…It is unclear if the strong immunogenicity of PDL241 was due to highly immunogenic amino acid sequences or the biology of the PDL241-CD319 interaction. The expression of CD319 on APC [11,38] may lead to enhanced presentation of humanized mAb leading to an enhanced ADA response. In support of this hypothesis, we have found that PDL241 was substantially more immunogenic in a huCD319 transgenic B57BL/6 mouse than in a wild-type B57BL/6 mouse (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…The ability of PDL241 to inhibit T cell function was not examined in this study; however, preliminary data support an inhibitory activity on T cell proliferation via depletion of CD319-expressing T cells. The expression of CD319 on pDC and mDC [38] may provide further therapeutic opportunities for anti-CD319 mAb. Although development of PDL241 was halted due to the immunogenicity concerns described above, our data highlight the potential of CD319 as a therapeutic target in a range of autoimmune diseases where CD319-expressing cells have a role in the pathology.…”

Section: Discussionmentioning

confidence: 99%

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PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

et al. 2013

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IntroductionTargeting the CD20 antigen has been a successful therapeutic intervention in the treatment of rheumatoid arthritis (RA). However, in some patients with an inadequate response to anti-CD20 therapy, a persistence of CD20- plasmablasts is noted. The strong expression of CD319 on CD20- plasmablast and plasma cell populations in RA synovium led to the investigation of the potential of CD319 as a therapeutic target.MethodsPDL241, a novel humanized IgG1 monoclonal antibody (mAb) to CD319, was generated and examined for its ability to inhibit immunoglobulin production from plasmablasts and plasma cells generated from peripheral blood mononuclear cells (PBMC) in the presence and absence of RA synovial fibroblasts (RA-SF). The in vivo activity of PDL241 was determined in a human PBMC transfer into NOD scid IL-2 gamma chain knockout (NSG) mouse model. Finally, the ability of PDL241 to ameliorate experimental arthritis was evaluated in a collagen-induced arthritis (CIA) model in rhesus monkeys.ResultsPDL241 bound to plasmablasts and plasma cells but not naïve B cells. Consistent with the binding profile, PDL241 inhibited the production of IgM from in vitro PBMC cultures by the depletion of CD319+ plasmablasts and plasma cells but not B cells. The activity of PDL241 was dependent on an intact Fc portion of the IgG1 and mediated predominantly by natural killer cells. Inhibition of IgM production was also observed in the human PBMC transfer to NSG mouse model. Treatment of rhesus monkeys in a CIA model with PDL241 led to a significant inhibition of anti-collagen IgG and IgM antibodies. A beneficial effect on joint related parameters, including bone remodeling, histopathology, and joint swelling was also observed.ConclusionsThe activity of PDL241 in both in vitro and in vivo models highlights the potential of CD319 as a therapeutic target in RA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

et al. 2013

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“…Expanded specific WT-1 126-134 ¡ T cells (Figs. 5 G-H) killed WT-1 126-134 , but not irrelevant KLK4 [11][12][13][14][15][16][17][18][19] peptide loaded T2 cells (Fig. 5I).…”

Section: Ivt-mrna Loaded Bdc Generate Primary Anti-viral and Antitumomentioning

confidence: 92%

“…myeloid dendritic cells (mDC) can be subdivided into three populations: CD1c C , CD141 C (or XCR1 C ) and CD16 C mDC subsets. [12][13][14][15] Given the phenotypic and functional heterogeneity of BDC subsets, [16][17][18] it still remains unclear which might be best for therapeutic vaccination. The major myeloid CD1c C DC have been isolated clinically using a two-step immune selection technology, but these isolations take a long time and the low yields limit the DC vaccination dose.…”

Section: Introductionmentioning

confidence: 99%

CMRF-56⁺blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

et al. 2016

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There are numerous transcriptional, proteomic and functional differences between monocyte-derived dendritic cells (Mo-DC) and primary blood dendritic cells (BDC). The CMRF-56 monoclonal antibody (mAb) recognizes a cell surface marker, which is upregulated on BDC following overnight culture. Given its unique ability to select a heterogeneous population of BDC, we engineered a human chimeric (h)CMRF-56 IgG4 mAb to isolate primary BDC for potential therapeutic vaccination. The ability to select multiple primary BDC subsets from patients and load them with in vitro transcribed (IVT) mRNA encoding tumor antigen might circumvent the issues limiting the efficacy of Mo-DC. After optimizing and validating the purification of hCMRF-56 C BDC, we showed that transfection of hCMRF-56 C BDC with mRNA resulted in efficient mRNA translation and antigen presentation by myeloid BDC subsets, while preserving superior DC functions compared to Mo-DC. Immune selected and transfected hCMRF-56 C BDC migrated very efficiently in vitro and as effectively as cytokine matured Mo-DC in vivo. Compared to Mo-DC, hCMRF-56 C BDC transfected with influenza matrix protein M1 displayed superior MHC peptide presentation and generated potent antigen specific CD8 C T-cell recall responses, while Wilms tumor 1 (WT1) transfected CMRF-56 C BDC generated effective primary autologous cytotoxic T-cell responses. The ability of the combined DC subsets within hCMRF-56 C BDC to present mRNA delivered tumor antigens merits phase I evaluation as a reproducible generic platform for the next generation of active DC immune therapies.

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“…2,32-36 Siglec-7 is expressed on a variety of immune cells, including NK-cells, T-cells, B-cells, eosinophiles, mast cells, basophils, monocytes, macrophages, dendritic cells, granulocytes, platelets and as well as on leukemic cells. 34,[36][37][38][39][40][41][42][43][44] After the discovery of Siglec-7 about 15 years ago, most functional studies focused mainly on its role on NK-cells or monocytes and most studies used anti-Siglec-7 antibodies, overexpression of the protein or global cellular changes in cis/trans ligands by enzymatic means. 36,37,[45][46][47][48][49] Although providing valuable information about Siglec-7 functions, results from these studies have to be assessed with care regarding the lectin function, due to the complex regulation of the sialoglycome and because antibodies are mostly unsuitable to study the physiological role of the interplay between the lectin domain and their carbohydrate ligands.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of 9- N -oxamyl sialosides as Siglec-7 ligands

Prescher

Gütgemann

Frank

et al. 2015

Bioorganic & Medicinal Chemistry

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Screening of the HLDA9 panel on peripheral blood dendritic cell populations

Cited by 7 publications

References 16 publications

PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

CMRF-56⁺blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

Synthesis and biological evaluation of 9- N -oxamyl sialosides as Siglec-7 ligands

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Screening of the HLDA9 panel on peripheral blood dendritic cell populations

Cited by 7 publications

References 16 publications

PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

CMRF-56+blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

Synthesis and biological evaluation of 9- N -oxamyl sialosides as Siglec-7 ligands

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Product

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CMRF-56⁺blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses