The Phylogeny of Proteinase 3/Myeloblastin, the Autoantigen in Wegener's Granulomatosis, and Myeloperoxidase as Shown by Immunohistochemical Studies on Human Leukemic Cell Lines

Müller‐Bérat, Nicole; Minowada, Jun; Tsuji-Takayama, Kazue; Drexler, Hans G.; Lanotte, Michel; Wieslander, Jörgen; Wiik, Allan

doi:10.1006/clin.1994.1010

Cited by 28 publications

(11 citation statements)

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“…On bone marrow cells from healthy donors, P3, NE, and PR1/HLA-A2 were coexpressed on myeloblasts ( Figure 2B and supplemental Figure 3A-B). 35 Low PR1/HLA-A2 expression was also observed on promyelocytes but not on maturing granulocytes, including metamyelocytes and band forms, despite high expression of P3 and NE ( Figure 2B and supplemental Figure 3). Because proteases are mostly localized in primary granules of mature granulocytes, 36 which limits MHC-I processing, and because transcription of P3 and NE is down-regulated in pro-myelocytes, 34,37 it is likely that MHC-I processing of newly synthesized P3 and NE proteins also decreases during maturation, preventing PR1 expression on mature granulocytes.…”

Section: F4 Antibody Identifies High Expression Of Pr1/hla-a2 On Myementioning

confidence: 98%

An anti–PR1/HLA-A2 T-cell receptor–like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells

Сергеева

Alatrash

et al. 2011

Blood

104

152

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PR1 (VLQELNVTV) is a human leukocyte antigen-A2 (HLA-A2)-restricted leukemiaassociated peptide from proteinase 3 (P3) and neutrophil elastase (NE) that is recognized by PR1-specific cytotoxic T lymphocytes that contribute to cytogenetic remission of acute myeloid leukemia (AML). We report a novel T-cell receptor (TCR)- IntroductionCD8 T cells specific for the human leukocyte antigen-A2 (HLA-A2)-restricted peptides WT1 and PR1, which are derived from the endogenous leukemia-associated antigens Wilms' tumor antigen [1][2][3] and proteinase 3 (P3), respectively, mediate cytotoxicity against acute myeloid leukemia (AML). PR1-specific T cells also contribute to cytogenetic remission of chronic myeloid leukemia (CML) in patients treated with interferon, 4,5 and vaccination with WT1 and PR1 6,7 can induce specific CD8 immunity in patients with myeloid malignancies. These results validate endogenous self-peptides as targets for immunotherapy, including vaccination, adoptive cell therapy, or antibodies that bind peptide/MHC. Such T-cell receptor (TCR)-like monoclonal antibodies (mAbs) may have selective activity against leukemia if target peptide/MHC complexes are aberrantly expressed on leukemia. Furthermore, mAbs are easy to administer and can be dosed frequently, which may increase their effectiveness against high leukemia burdens.Eliciting TCR-like mAbs has been technically challenging, 8 primarily because of the high immunogenicity of HLA molecules in mice. Phage-display libraries, 9 peptide/MHC immunization, 10,11 and the combination of both strategies 8,12 have been used to produce TCR-like mAbs targeting peptides derived from solid-tumor antigens (eg, MAGE, ␤-HCG, TARP, and NY-ESO-1) in the context of HLA-A1 or HLA-A2. [9][10][11]13,14 Although antibody activity against primary tumors has not been well studied, complement-dependent cytotoxicity (CDC) against tumor cell lines has been reported. 11 Some toxin-conjugated antibodies also show activity against tumor cells. 14-16 However, to eradicate cancer, these antibodies must be active against cancerinitiating cells, and TCR-like mAb-induced cytolysis of cancer stem cells has not been reported. Nevertheless, because PR1-specific CTLs suppress leukemia progenitor cells in vitro 17 and because Lin Ϫ CD34 ϩ CD38 Ϫ cells are enriched for leukemia stem cells (LSCs) 18 and can be easily studied, we hypothesized that if an anti-PR1/HLA-A2 antibody could be produced, it may be active against blasts and LSCs from HLA-A2 ϩ AML patients.We report the discovery of 8F4, a novel mAb that binds with high affinity to a conformational epitope of PR1/HLA-A2 and induces dose-dependent cytolysis of myeloid leukemia cells but not normal hematopoietic cells. 8F4 mediates CDC against Lin Ϫ CD34 ϩ CD38 Ϫ LSCs and preferentially inhibits the growth of leukemia progenitor cells. These results justify further study of TCR-like antibodies to verify the differential effects against normal stem cells and LSCs. Biologically significant differences may justify further study of a humanized form o...

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Section: F4 Antibody Identifies High Expression Of Pr1/hla-a2 On Myementioning

confidence: 98%

An anti–PR1/HLA-A2 T-cell receptor–like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells

Сергеева

Alatrash

et al. 2011

Blood

104

152

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“…These serine proteases are stored in the primary azurophilic granules and are normally overexpressed at the promyelocyte stage of myeloid differentiation. [18][19][20] Interestingly, PRTN3 appears to be important in maintaining the leukemogenic phenotype as its inhibition by the use of antisense oligonucleotides halts cell division and induces terminal differentiation of the HL-60 promyelocytic leukemia cell line. 21 In addition, both PRTN3 and ELA2 are believed to be the antigens recognized by autoreactive pathogenic T-and B-lymphocyte clones associated with Wegener's granulomatosis and possibly other small-vessel vasculitides syndromes.…”

Section: Potential Myeloid Leukemia-associated Antigensmentioning

confidence: 99%

Immunotherapy for myeloid leukemias: current status and future directions

El-Shami

Smith

2008

Leukemia

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Myeloid leukemias, although a heterogeneous group of hematopoietic stem cell neoplasms, are arguably among the most suited for active specific immunotherapy. Nevertheless, clinical development of myeloid leukemia vaccine lagged behind similar approaches in other solid and hematological malignancies. The recent identification of apparently specific leukemia antigens and advances in understanding the fundamentals of tumor immunology have helped initiate a number of early phase clinical studies evaluating the safety and clinical efficacy of this approach. Here we review the recently identified and characterized putative leukemia antigens, the main vaccination strategies employed by most investigators and the results of clinical studies of immunotherapy of myeloid leukemias. Although these studies are early and often difficult to interpret, they offer evidence that effective immunity to leukemia could be induced following vaccination, and that clinical benefit can sometimes be observed, thus setting the stage for future development of this strategy and in the combinatorial approaches to treatment of myeloid leukemias that incorporate immunotherapy.

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“…21 The 29 kDa protein degrades extracellular matrix proteins such as collagen type IV, elastin, fibronectin, vitronectin, and laminin, 22,23 is detectable in normal granulocytes, a fraction of monocytes, and precursor cells of phagocytes. 24,25 At the promyelocytic stage, Mbn may play a key role for initiation of terminal differentiation. 10 Whether this is functionally linked to the often marked leukocytosis of acute phase Wegener's granulomatosis is an intriguing albeit open question.…”

Section: Introductionmentioning

confidence: 99%

True

1999

Leukemia

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The Phylogeny of Proteinase 3/Myeloblastin, the Autoantigen in Wegener's Granulomatosis, and Myeloperoxidase as Shown by Immunohistochemical Studies on Human Leukemic Cell Lines

Cited by 28 publications

References 0 publications

An anti–PR1/HLA-A2 T-cell receptor–like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells

An anti–PR1/HLA-A2 T-cell receptor–like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells

Immunotherapy for myeloid leukemias: current status and future directions

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