The CD19 Antibody MOR208 Efficiently Triggers Natural Killer Cell-Mediated Cytotoxicity Against Acute Lymphoblastic Leukemia Cells From Pediatric and Adult Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1502-1502
Author(s):  
Christian Kellner ◽  
Eugene A Zhukovsky ◽  
Monika Brüggemann ◽  
Michael Kneba ◽  
André Schrauder ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Lymphoblastic Leukemia ◽  
Killer Cell ◽  
Adult Patients ◽  
Target Antigen ◽  
Target Cells ◽  
Effector Cells

Abstract Abstract 1502 CD19 represents a promising target antigen for therapeutic antibodies in the treatment of B-lineage acute lymphoblastic leukemia (ALL), because it is expressed very early during B-cell development and thus is highly displayed by the majority of both precursor and mature B-ALL cells. Several CD19-targeting molecules are in different stages of preclinical and clinical development. However, no conventional CD19 antibodies have been approved to date for clinical application. This may be due to the limited effector functions triggered by the wild type Fc-domain of first generation CD19 antibodies. These limitations may be overcome by next generation antibodies with enhanced potency such as MOR208 (formerly XmAb5574), an Fc-engineered humanized CD19 antibody that has shown high activity in preclinical models of multiple B cell neoplasms and is currently evaluated in a phase I clinical trial in chronic lymphocytic leukemia. Here, MOR208 and its non-engineered IgG1 analogue were evaluated for their potential to trigger antibody-dependent cell-mediated cytotoxicity (ADCC) of freshly isolated ALL cells from both pediatric and adult patients. To quantify Fc-mediated effector function, MOR208 and its native IgG1 analogue were evaluated for their ability to induce lysis of primary ALL cells in standard 51Cr release assays using different effector cell populations, or human serum as a source of complement. MOR208 induced potent ADCC in the presence of natural killer (NK) cells, whereas no cytotoxicity was observed for either CD19 antibody when myeloid effector cells were used. Neither antibody triggered complement-dependent cytotoxicity. MOR208 induced NK-cell mediated lysis of a panel of freshly isolated ALL samples obtained from seven adult and eight pediatric ALL patients. MOR208 triggered lysis at picomolar concentrations (EC50 = 26 pM) and was more effective than the native CD19 IgG1 analogue. MOR208 activated NK cells more potently as indicated by upregulation of CD69. In addition, MOR208 required lower effector-to-target cell ratios and antibody concentrations, and achieved higher maximum extents of lysis (30% and 15% target cells lysis by MOR208 and the native CD19 IgG1 analogue, respectively). The improved ADCC potential of NK cells was observed irrespective of the FcγRIIIA allotype at amino acid position 158. Moreover, MOR208 induced ADCC with patient-derived NK cells and mediated lysis of autologous ALL cells despite expression of inhibitory MHC class I molecules. MOR208 also displayed high cytotoxicity with allogeneic donor-derived NK cells isolated from a patient previously transplanted with allogeneic hematopoietic progenitor cells. These experiments demonstrate that MOR208 exhibits enhanced cytotoxicity compared to a native non-engineered anti-CD19 antibody when employing patient-derived tumor cells. CD19 antibody therapy with MOR208 may represent a promising approach for the treatment of pediatric or adult B-ALL, by overcoming the limitations of conventional CD19 antibodies. Application of MOR208 may be especially promising in the eradication of minimal residual disease cells in a post-transplantation context where high numbers of allogeneic NK effector cells are available. Disclosures: Zhukovsky: Xencor, Inc. / Affimed Therapeutics AG: Employment.

scholarly journals NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1420
Author(s):  
Jagoda Siemaszko ◽  
Aleksandra Marzec-Przyszlak ◽  
Katarzyna Bogunia-Kubik
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Bacterial Infections ◽  
Killer Cell ◽  
Cell Receptor ◽  
Target Cells ◽  
Effector Cells ◽  
Stressed Cells ◽  
The Right ◽  
Nkg2d Receptor

Natural Killer (NK) cells are natural cytotoxic, effector cells of the innate immune system. They can recognize transformed or infected cells. NK cells are armed with a set of activating and inhibitory receptors which are able to bind to their ligands on target cells. The right balance between expression and activation of those receptors is fundamental for the proper functionality of NK cells. One of the best known activating receptors is NKG2D, a member of the CD94/NKG2 family. Due to a specific NKG2D binding with its eight different ligands, which are overexpressed in transformed, infected and stressed cells, NK cells are able to recognize and attack their targets. The NKG2D receptor has an enormous significance in various, autoimmune diseases, viral and bacterial infections as well as for transplantation outcomes and complications. This review focuses on the NKG2D receptor, the mechanism of its action, clinical relevance of its gene polymorphisms and a potential application in various clinical settings.

Artificial Antigen Presenting Cells (aAPC) Expanded NK-Mediated Enhanced Lysis of Allogeneic Tumor Cells Regardless of HLA Class I/KIR Mismatch and Its Implication of Use in Eradicating Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3023-3023
Author(s):  
Hua Zhang ◽  
Bruce Levine ◽  
Nga Voong ◽  
Alan S. Wayne ◽  
Carl H. June ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Fusion Proteins ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Target Cells ◽  
Activating Receptors

Abstract Abstract 3023 Poster Board II-999 NK Killer cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen (HLA) ligands play critical roles in maintaining natural killer (NK) cell tolerance, while providing surveillance against pathogens and malignant transformation. Natural killer (NK) cells have been explored as tools for adoptive anti-tumor or leukemia immunotherapy and current models hold that a mismatch or absence of KIR ligands on target cells is essential for efficient NK cell mediated cytolysis. However, new approaches are now available to activate NK cells and the role for KIR mediated signaling in regulating cytotoxicity of activated NK cells has not been well studied. In this study, aAPCs comprising IL15Ra+K562 cells engineered to express 4-1BBL activated and expanded peripheral NK cells in the presence of exogenous IL15 up to 1000-fold in 3 weeks. Compared to resting NK cells, 4-1BBL/IL15-activated NK cells upregulated TRAIL and NKp30, 44, 46 expression, and showed significantly enhanced cytotoxicity against a multitude of tumor targets including K562, Daudi, Ewing's tumors, osteosarcoma, as well as autologous tumors (50%-90% killing vs. 0%-8% with non-activated NK cells). Meanwhile we could detect little to no influence of KIR signaling in regulating cytotoxicity by aAPC activated NK cells, since sorted CD158a+ and CD158b+ activated NK cells showed similar killing of tumor cells expressing HLA group C1 (CD158b ligand) and/or C2 (CD158a ligand) antigens. In contrast, killer activating receptors (KARs) were indispensable for the cytolysis of solid pediatric tumors by aAPC-activated NK cells, since the killing was significantly inhibited by fusion proteins binding to the ligands of NKG2D, NK p30, p44, p46, p80 (KARs). About 20-40% inhibition of the killing was accomplished when all four activating receptors were blocked, though other activating receptors have not been well defined. Although acute lymphoblastic leukemia (ALL) blasts were refractory to fresh NK cytotoxicity, 4-1BBL/IL15 activated NK cells demonstrated higher lytic activities (20%-50%) against ALL blasts from either patients or cell lines. ALL blast lysis could be completely or partially inhibited by KAR-blocking fusion proteins, indicating that expression levels of KAR ligands vary among ALL cases and other solid tumors. We conclude that KIR ligand mismatch or absence is not essential for effective NK cytotoxicities on either solid tumors or ALL when fully activated NK cells are utilized. This suggests that adoptive therapy with autologous aAPC-activated NK cells may prove effective in some clinical settings, such as ALL, AML, or certain solid tumors. Further studies to assess the impact of KAR ligand expression on aAPC-activated NK killing of ALL blasts are in progress. Percentage of Activated NK Killings vs. Fresh NK's with/without KAR-Ig Fusion Proteins Activated NK (E:T=2.5:1) Fresh NK (E:T=25:1) -KAR-Ig Fc +KAR-Ig Fc SB tumor (Ewing's) 48% 30% 0.5% HOS (Osteo sarcoma) 63% 36% 0.7% Daudi (B. lymphoma) 78% 46% 0.2% REH (ALL) 54% 8% 3% Disclosures No relevant conflicts of interest to declare.

The ABCs of Immunotherapy for Adult Patients With B-Cell Acute Lymphoblastic Leukemia

2017 ◽  
Vol 52 (3) ◽  
pp. 268-276 ◽  
Author(s):  
Troy Z. Horvat ◽  
Amanda N. Seddon ◽  
Adebayo Ogunniyi ◽  
Amber C. King ◽  
Larry W. Buie ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Data Extraction ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Efficacy And Safety ◽  
Car T Cells ◽  
Car T ◽  
American Society

Objective: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). Data Sources: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR). Study Selection/Data Extraction: Studies of pharmacology, clinical efficacy, and safety of rituximab, ofatumumab, obinutuzumab, inotuzumab, blinatumomab, and CAR T-cells in the treatment of adult patients with ALL were identified. Data Synthesis: Conventional chemotherapy has been the mainstay in the treatment of ALL, producing cure rates of approximately 90% in pediatrics, but it remains suboptimal in adult patients. As such, more effective consolidative modalities and novel therapies for relapsed/refractory disease are needed for adult patients with ALL. In recent years, anti-CD20 antibodies, blinatumomab, inotuzumab, and CD19-targeted CAR T-cells have drastically changed the treatment landscape of B-cell ALL. Conclusion: Outcomes of patients with relapsed disease are improving thanks to new therapies such as blinatumomab, inotuzumab, and CAR T-cells. Although the efficacy of these therapies is impressive, they are not without toxicity, both physical and financial. The optimal sequencing of these therapies still remains a question.

scholarly journals Ultrastructural analysis of human natural killer cell activation

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1725-1736 ◽  
Author(s):  
D Zarcone ◽  
EF Prasthofer ◽  
F Malavasi ◽  
V Pistoia ◽  
AF LoBuglio ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Nk Cells ◽  
Natural Killer ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Ultrastructural Changes ◽  
Target Cells ◽  
Resting Cells ◽  
Human Natural Killer Cell ◽  
Dense Granules

In this study we describe characteristic ultrastructural changes of CD3- large granular lymphocytes (LGL), ie, natural killer (NK) cells, following stimulation with recombinant (r) interleukin 2 (IL 2) or r- gamma interferon (r-gamma IFN) and after interaction with K562 target cells (TC) or Sepharose-bound anti-Fc gamma receptor (FcR) monoclonal antibody (MoAb). When compared to resting cells the cytolytic activity of r-IL 2- and r-gamma IFN-stimulated cells against K562 TC was enhanced. The r-IL 2-stimulated LGL were larger and consistently displayed the shape and cytoskeletal rearrangement characteristic of activated cells. The Golgi apparatus was expanded, and the number of electron-dense granules and vesicles was increased. The ultrastructural changes in r-gamma IFN-stimulated LGL were markedly different from those observed following r-IL 2 activation. Cells did not exhibit changes in size, shape, cytoskeletal organization, or in the structure of the Golgi apparatus. However, r-gamma IFN-stimulated cells exhibited distinctive changes in the structure and content of electron-dense granules with deaggregation of the matrix and parallel tubular arrays (PTAs). Within organelles apparently derived from the electron-dense granules, vesicular and tubular structures were noted that may be the morphological equivalent of cytotoxic factors produced by cytolytic effector cells. These ultrastructural observations indicate that r-IL 2 and r-gamma IFN enhance the lytic ability of NK cells by acting on distinct cell machineries. The cytolytic ability was decreased when LGL were pretreated with K562 TC or immobilized anti-FcR antibody. In both experimental conditions cells displayed ultrastructural features indicating activation as well as loss of cytoplasmic granules and other Golgi-derived organelles. Stimulation of r-gamma IFN- or r-IL 2- activated LGL with K562 TC or Sepharose-bound anti-FcR antibody decreased their cytolytic ability, with cells depleted of granules at the ultrastructural level. Intracytoplasmic fusion of granules and a massive release of the granule content were found in r-IL 2-stimulated cells, reminiscent of the mechanism of basophil degranulation. These observations suggest that multiple activation signals involving distinct surface membrane molecules induce release of cytolytic factors by both resting and activated NK cells.

scholarly journals Sensitizing primary acute lymphoblastic leukemia to natural killer cell recognition by induction of NKG2D ligands

2012 ◽  
Vol 54 (1) ◽  
pp. 167-173 ◽  
Author(s):  
Laura Jardine ◽  
Sophie Hambleton ◽  
Venetia Bigley ◽  
Sarah Pagan ◽  
Xiao-Nong Wang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Lymphoblastic Leukemia ◽  
Killer Cell ◽  
Cell Recognition ◽  
Nkg2d Ligands

scholarly journals CRLF2-Positive B-Cell Acute Lymphoblastic Leukemia in Adult Patients

2017 ◽  
Vol 147 (4) ◽  
pp. 357-363 ◽  
Author(s):  
Sergej Konoplev ◽  
Xinyan Lu ◽  
Marina Konopleva ◽  
Nitin Jain ◽  
Juan Ouyang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype.

1996 ◽  
Vol 183 (4) ◽  
pp. 1817-1827 ◽  
Author(s):  
J E Gumperz ◽  
N M Valiante ◽  
P Parham ◽  
L L Lanier ◽  
D Tyan
Keyword(s):  
T Cells ◽  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Killer Cell ◽  
Peripheral Blood Lymphocytes ◽  
Class I ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Hla Type

Natural killer (NK) cells that express the NKB1 receptor are inhibited from killing target cells that possess human histocompatibility leukocyte antigen (HLA) B molecules bearing the Bw4 serological epitope. To investigate whether NKB1 expression is affected by HLA type, peripheral blood lymphocytes of 203 HLA-typed donors were examined. Most donors had a single population of NKB1+ cells, but some had two populations expressing different cell surface levels of NKB1, and others had no detectable NKB1+ cells. Among the donors expressing NKB1, both the relative abundance of NKB1+ NK cells and their level of cell surface expression varied substantially. The percentage of NKB1+ NK cells ranged from 0 to >75% (mean 14.7%), and the mean fluorescence of the positive population varied over three orders of magnitude. For each donor, the small percentage of T cells expressing NKB1 (usually <2%), had a pattern of expression mirroring that of the NK cells. NKB1 expression by NK and T cells remained stable over the 2-yr period that five donors were tested. Patterns of NKB1 expression were not associated with Bw4 or Bw6 serotype of the donor or with the presence of any individual HLA-A or -B antigens. Cells expressing NKB1 are often found in donors who do not possess an appropriate class I ligand, and can be absent in those who express Bw4+ HLA-B antigens. Family studies further suggested that the phenotype of NKB1 expression is inherited but not HLA linked. Whereas identical twins show matching patterns of NKB1 expression, HLA-identical siblings can differ in NKB1 expression, and conversely, HLA-disparate siblings can be similar. Thus NKB1 expression phenotypes are tightly regulated and extremely heterogeneous, but not correlated with HLA type.

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