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  • 2015-2019  (3)
  • 1
    Publication Date: 2018-08-21
    Description: Controlling immune responses in autoimmunity and to biotherapeutics is an unmet need. In hemophilia, for example, up to one third of patients receiving therapeutic factor VIII (FVIII) infusions develop neutralizing Abs termed "inhibitors." To address this problem in a mouse model of hemophilia A, we used an Ag-specific regulatory T cell (Treg) approach in which we created a novel B cell–targeting chimeric receptor composed of an FVIII Ag domain linked with the CD28-CD3 transmembrane and signaling domains. We termed these "BAR" for B cell–targeting Ab receptors. CD4 + CD25 hi CD127 low human Tregs were retrovirally transduced to express a BAR containing the immunodominant FVIII C2 or A2 domains (C2- and A2-BAR). Such BAR-Tregs specifically suppressed the recall Ab response of spleen cultures from FVIII-immunized mice in vitro and completely prevented anti-FVIII Ab development in response to FVIII immunization. Mechanistic studies with purified B cells and T cells from tolerized or control recipients demonstrated that the FVIII-specific B cells were directly suppressed or anergized, whereas the T cell response remained intact. Taken together, we report in this study a successful proof-of-principle strategy using Ag-expressing Tregs to directly target specific B cells, an approach which could be adapted to address other adverse immune responses as well.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 2
    Publication Date: 2018-09-05
    Description: Clinical application of Ag-specific T regulatory cells (Tregs) offers promise for the treatment of undesirable immune diseases. To achieve this goal, long-term expansion of Tregs is required to obtain sufficient numbers of cells. However, human Tregs are not stable ex vivo. Therefore, we previously developed an innovative Treg expansion protocol using 25mer-phosphorothioated random oligonucleotides (ODNps25). The addition of ODNps25 successfully resulted in the stabilization of engineered Ag-specific Tregs; however, the mechanism is not fully characterized. We first identified sterile α motif histidine-aspartate–domain containing protein 1 (SAMHD1) as an ODNps25-binding protein using a UV–cross-linking pull-down strategy. SAMHD1 physically interacted with the 3' untranslated region of Foxp3 mRNA and was translocated from nucleus to cytoplasm after ODNps25 treatment. Importantly, addition of ODNps25 enhanced the interaction of SAMHD1 and Foxp3 mRNA significantly, and this interaction was increased by TCR stimulation. Because ODNps25 binds to the nuclease (HD) domain of SAMHD1, we then established that overexpression of a dNTPase-deficient mutant (D137N) in Tregs significantly stabilized the expression level of the Foxp3 protein. Furthermore, we found that TCR stimulation upregulates phosphorylation of the threonine residue (Thr592), which is a regulatory site to control SAMHD1 activity, and phosphorylation of Thr592 is critical to control SAMHD1 activity to stabilize the expression of Foxp3 and Helios in Tregs. Taken together, we suggest that the interaction of ODNPs25 in HD or phosphorylation of Thr592 by TCR stimulation interferes with nuclease activity of SAMHD1, thereby stabilizing 3' untranslated region of Foxp3 and Helios mRNAs in long-term culture.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 3
    Publication Date: 2018-01-03
    Description: Hematologically derived tumors make up ~10% of all newly diagnosed cancer cases in the United States. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1. CD22 is a clinically validated target for the treatment of NHL, but no anti-CD22 agents have yet been approved for this indication. Recent approval of an anti-CD22 antibody–drug conjugate (ADC) for the treatment of relapsed/refractory ALL supports the rationale for targeting this protein. An opportunity exists for a next-generation anti-CD22 antibody–drug conjugate (ADC) to address unmet medical needs in the relapsed/refractory NHL population. We describe a site-specifically conjugated antibody–drug conjugate, made using aldehyde tag technology, targeted against CD22 and bearing a noncleavable maytansine payload that is resistant to MDR1-mediated efflux. The construct was efficacious against CD22 + NHL xenografts and could be repeatedly dosed in cynomolgus monkeys at 60 mg/kg with no observed significantly adverse effects. Exposure to total ADC at these doses (as assessed by AUC 0-inf ) indicated that the exposure needed to achieve efficacy was below tolerable limits. Together, the data suggest that this drug has the potential to be used effectively in patients with CD22 + tumors that have developed MDR1-related resistance to prior therapies. Mol Cancer Ther; 17(1); 161–8. ©2017 AACR .
    Print ISSN: 1535-7163
    Electronic ISSN: 1538-8514
    Topics: Medicine
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