Monoclonal antibodies to LFA-I molecule beta-chain promote a rise in the cytotoxic index of effector cells and stimulate their proliferation

1993 ◽  
Vol 115 (6) ◽  
pp. 718-720
Author(s):  
I. A. Popov ◽  
N. G. Anosova ◽  
A. A. Bakova ◽  
B. D. Brondz ◽  
Y. S. Krivoshein ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Beta Chain ◽  
Effector Cells ◽  
Cytotoxic Index

scholarly journals Antibody-based therapy of leukaemia

2009 ◽  
Vol 11 ◽  
Author(s):  
John C. Morris ◽  
Thomas A. Waldmann
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cell ◽  
Gemtuzumab Ozogamicin ◽  
Cell Leukaemia ◽  
Target Cells ◽  
Immune Effector ◽  
Effector Cells ◽  
Prolymphocytic Leukaemia ◽  
Immune Effector Cells

Over the past decade, monoclonal antibodies have dramatically impacted the treatment of haematological malignancies, as evidenced by the effect of rituximab on the response rate and survival of patients with follicular and diffuse large B cell non-Hodgkin's lymphoma. Currently, only two monoclonal antibodies – the anti-CD33 immunotoxin gemtuzumab ozogamicin and the CD52-directed antibody alemtuzumab – are approved for treatment of relapsed acute myeloid leukaemia in older patients and B cell chronic lymphocytic leukaemia, respectively. Although not approved for such treatment, alemtuzumab is also active against T cell prolymphocytic leukaemia, cutaneous T cell lymphoma and Sézary syndrome, and adult T cell leukaemia and lymphoma. In addition, rituximab has demonstrated activity against B cell chronic lymphocytic and hairy cell leukaemia. Monoclonal antibodies targeting CD4, CD19, CD20, CD22, CD23, CD25, CD45, CD66 and CD122 are now being studied in the clinic for the treatment of leukaemia. Here, we discuss how these new antibodies have been engineered to reduce immunogenicity and improve antibody targeting and binding. Improved interactions with Fc receptors on immune effector cells can enhance destruction of target cells through antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. The antibodies can also be armed with cellular toxins or radionuclides to enhance the destruction of leukaemia cells.

Antibody Therapeutics for Ovarian Carcinoma and Translation to the Clinic

2018 ◽  
Author(s):  
Debra H. Josephs ◽  
Heather J. Bax ◽  
Giulia Pellizzari ◽  
James F. Spicer ◽  
Ana Montes ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Monoclonal Antibodies ◽  
Tumor Antigens ◽  
Ovarian Carcinomas ◽  
Immune Effector ◽  
Effector Cells ◽  
Tumor Microenvironments ◽  
Specific Tumor ◽  
Anti Cancer ◽  
Reduced Toxicity

Despite improvements over the past decade in the treatment of ovarian cancer, many patients are at risk of recurrent disease and emerging drug resistance. The increased selectivity and reduced toxicity of molecularly targeted anti-cancer agents renders them attractive for development in ovarian cancer, and monoclonal antibodies targeting ovarian cancer-specific tumor antigens represent the largest such group investigated in this clinical setting. This chapter describes examples of monoclonal antibodies clinically evaluated for efficacy in ovarian cancer. These agents recognize molecular targets expressed on tumors or within tumor microenvironments that may be essential for tumor cell survival and proliferation. Recently, antibodies targeting checkpoint molecules on immune cells have shown efficacy in modulating anti-tumor immunity, and applications in ovarian carcinomas are evaluated. The chapter focuses on therapeutic agents’ attributes on targeting key cancer growth and progression pathways, and propensity to engender effector functions by activating immune effector cells in tumors and the circulation.

scholarly journals Enhancing antibody-dependent cell-mediated cytotoxicity: a strategy for improving antibody-based immunotherapy

2018 ◽  
Vol 1 (1) ◽  
pp. 7-12 ◽  
Author(s):  
David Zahavi ◽  
Dalal AlDeghaither ◽  
Allison O’Connell ◽  
Louis M Weiner
Keyword(s):  
Monoclonal Antibodies ◽  
Mechanism Of Action ◽  
Clinical Performance ◽  
Cancer Therapeutics ◽  
Surface Antigens ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Dependent Cell ◽  
Antibody Design

ABSTRACT The targeting of surface antigens expressed on tumor cells by monoclonal antibodies (mAbs) has revolutionized cancer therapeutics. One mechanism of action of antibody-based immunotherapy is the activation of immune effector cells to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). This review will summarize the process of ADCC, its important role in the efficacy of mAb therapy, how to measure it, and finally future strategies for antibody design that can take advantage of it to improve clinical performance.

Monoclonal antibodies with cytotoxic reactivities against human gliomas

1989 ◽  
Vol 71 (6) ◽  
pp. 892-897 ◽  
Author(s):  
Anil Nanda ◽  
Boleslaw Liwnicz ◽  
Barbara F. Atkinson ◽  
Ben-Ami Sela ◽  
Hiroshi Takahashi ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Malignant Glioma ◽  
Bone Marrow Cells ◽  
Human Lymphocytes ◽  
Glioma Cells ◽  
Immunofluorescence Assay ◽  
Normal Brain ◽  
Content Type ◽  
Effector Cells ◽  
Human Malignant Glioma

✓ Monoclonal antibodies (MAb's) reactive with human malignant glioma cells were derived from mice inoculated with cells from fresh glioma tissue. Seven MAb's were selected for study based on their high-level binding in immunoperoxidase and immunofluorescence assay to most of the glioma tissues derived from various patients and based on the absence of binding to normal bone marrow cells. Four of the seven MAb's did not bind to any of the four normal brain tissues tested, whereas three MAb's bound to one or two of these tissues. Two MAb's bound to the surfaces of cultured glioma cells in radioimmunoassay. One of these MAb's (AS-AY1, immunoglobulin (Ig)G1) lysed cultured glioma cells with human lymphocytes or murine macrophages as effector cells; the other MAb (AS-AY2, IgM) was reactive in complement-dependent cytotoxicity assay. These two MAb's therefore seem especially promising reagents in approaches to immunotherapy of human malignant glioma.

scholarly journals Monoclonal Antibodies in Gynecological Cancer: A Critical Point of View

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Filippo Bellati ◽  
Chiara Napoletano ◽  
Maria Luisa Gasparri ◽  
Valeria Visconti ◽  
Ilaria Grazia Zizzari ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Folate Receptor ◽  
Gynecological Cancer ◽  
Female Genital Tract ◽  
Growth Factor Receptor ◽  
Point Of View ◽  
Immune Effector ◽  
Effector Cells ◽  
Cancer Cell Survival

During the last decades, several improvements in treating gynecological malignancies have been achieved. In particular, target therapies, mostly monoclonal antibodies, have emerged as an attractive option for the treatment of these malignancies. In fact, various molecular-targeted agents have been developed for a variety of malignancies with the objective to interfere with a precise tumor associated receptor, essential for cancer cell survival or proliferation, blocking its function, of the cancer cells. Alternatively, monoclonal antibodies have been developed to block immune suppression or enhance functions of immune effector cells. So far, several monoclonal antibodies have been tested for clinical efficacy for the treatment of gynecological cancers. Antibodies against Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) have been used in different neoplasms such as ovarian and cervical cancer. Catumazumab, a bivalent antibody against CD3 and EpCAM, is effective in the treatment of neoplastic ascites. Other antibodies are peculiar for specific cancer-associated antigen such as Oregovomab against CA125 or Farletuzumab against the folate receptor. Here we describe the preclinical and clinical experience gained up to now with monoclonal antibodies in tumors of the female genital tract and trace future therapeutic and research venues.

Immunohistochemical Detection of c-erbB-2 Expression by Neoplastic Human Tissue using Monospecific and Bispecific Monoclonal Antibodies

1993 ◽  
Vol 8 (4) ◽  
pp. 233-239 ◽  
Author(s):  
I. Garcia De Palazzo ◽  
A. Klein-Szanto ◽  
L. M. Weiner
Keyword(s):  
Monoclonal Antibodies ◽  
Malignant Tumors ◽  
Prognostic Indicator ◽  
Wide Distribution ◽  
Ovarian Carcinomas ◽  
Effector Cells ◽  
Antibody Binding Site ◽  
Neu Oncogene ◽  
Tumor Expression

Selected murine monoclonal antibodies (MAb) have been shown to inhibit relevant tumor growth in vitro and in animal models. Recently, bispecific antibodies (BsMAb) have been developed which target cytolytic effector cells via one antibody binding site and tumor antigen by the other specificity. For example, the BsMAb 2B1 possesses specificity for c-erbB-2 and Fcγ RIII, the low affinity Fcγ receptor expressed by polymorphonuclear leukocytes (PMN), macrophages and large granular lymphocytes (LGL). The human homologue of the rat neu oncogene, c-erbB-2, has been demonstrated to be amplified in breast, gastrointestinal, lung and ovarian carcinomas. Tumor expression of c-erbB-2 has been shown to be an important prognostic indicator in breast and ovarian carcinomas. The restricted expression of the c-erbB-2 protooncogene product in normal human tissues and the wide distribution of c-erbB-2 expression in such tumors may justify attempts to use an appropriately constructed BsM Ab in clinical trials. In this report we have addressed this issue by immunohistochemically evaluating the expression of c-erbB-2 oncogene product in a variety of malignant tumors utilizing 2B1 and the anti-c-erbB-2 monovalent parent of 2B1, 520C9. Among the studied neoplasms, c-erbB-2 expression was detected in 49% of primary carcinomas stained with 520C9 and in 39% of those stained with 2B1. In the group of metastatic tumors, c-erbB-2 oncoprotein was detected in 52% of cases by 520C9 and in 41% by 2B1. Our results indicate that immunocytochemistry using bispecific monoclonal 2B1 is a reliable method for the detection of c-erbB-2 expression, and that this BsMAb detects c-erbB-2 expression in tumors nearly as well as its anti-c-erbB-2 monovalent parent antibody.

scholarly journals Characterization of patients with an increased susceptibility to bacterial infections and a genetic deficiency of leukocyte membrane complement receptor type 3 and the related membrane antigen LFA-1

Blood ◽  
1985 ◽  
Vol 66 (4) ◽  
pp. 882-890 ◽  
Author(s):  
GD Ross ◽  
RA Thompson ◽  
MJ Walport ◽  
TA Springer ◽  
JV Watson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Bacterial Infections ◽  
Nk Cell ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Beta Chain ◽  
Alpha Chain ◽  
The Common ◽  
Respiratory Responses ◽  
Increased Susceptibility

Abstract Three children from two unrelated families had a history of recurrent bacterial infections, and their neutrophils were shown to have deficient phagocytic and respiratory responses and possible deficiencies in chemotaxis or adherence. Their neutrophils were strikingly deficient in the ability to ingest or give a respiratory burst in response to unopsonized bakers' yeast or zymosan (Z). Tests for neutrophil and monocyte CR1 (C3b/iC3b receptor) and CR3 (iC3b receptor) demonstrated rosettes with both EC3b and EC3bi. However, EC3bi were bound only to CR1, and not to CR3, because EC3bi rosettes were inhibited completely by anti-CR1. Neutrophils, monocytes, and natural killer (NK) cells also did not fluorescence stain with monoclonal antibodies specific for the alpha-chain of CR3 (anti-Mac-1, anti-Mol, OKM1, and MN-41). Quantitation of C receptors with 125I monoclonal anti-CR1 and anti-CR3 indicated that neutrophils from each patient expressed normal amounts of CR1 per cell but less than 10% of the normal amount of CR3. Examination of neutrophils by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated that a normal glycoprotein of approximately 165,000 daltons was missing. Immunoblotting of these gels indicated that the missing band was the alpha-chain of CR3. Subsequent analysis of all three patients' cells also demonstrated a deficiency of LFA-1 alpha-chain and the common beta- chain that is shared by the CR3/LFA-1/p150,95 membrane antigen family. The deficiency of LFA-1 probably explained the absent NK cell function, as normal NK cell activity is inhibited by anti-LFA-1 but not by anti- CR3. The reduced phagocytic and respiratory responses to Z were probably due to CR3 deficiency, because treatment of normal neutrophils with anti-CR3, but not anti-FLA-1, inhibits responses to Z by 80% to 90%. Ingestion of Staphylococcus epidermidis by normal neutrophils was shown to be partially inhibited by monoclonal antibodies to the alpha- chain of either CR3 or LFA-1, and monoclonal antibody to the common beta-chain inhibited ingestion by 75%. Thus, both CR3 and LFA-1 may have previously unrecognized functions as phagocyte receptors for bacteria. The absence of this type of nonimmune recognition of bacteria by these children's neutrophils may be one of the reasons for their increased susceptibility to bacterial infections.

scholarly journals Lymphokine-activated killer cell phenomenon. II. Precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymus-derived lymphocytes, and natural killer cells

1983 ◽  
Vol 157 (3) ◽  
pp. 884-897 ◽  
Author(s):  
EA Grimm ◽  
KM Ramsey ◽  
A Mazumder ◽  
DJ Wilson ◽  
JY Djeu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
T Lymphocytes ◽  
Natural Killer ◽  
Tumor Cells ◽  
Nk Cell ◽  
Precursor Cells ◽  
Cell Phenotype ◽  
Killer Cells ◽  
Effector Cells

Culture of human peripheral blood lymphocytes (PBL) in partially purified and lectin-free interleukin 2 results in the generation of cytotoxic effector cells which have the unique property of lysing natural killer (NK)-resistant fresh human tumor cells. We have termed these effector cells "lymphokine- activated killer" cells (LAK). LAK are generated from both normal and cancer patients' PBL and are able to lyse both autologous and allogeneic tumor cells from all histologic tumor types tested. Our previous studies suggested that the LAK phenomenon was distinct from either the cytotoxic thymus-derived lymphocyte (CTL) or NK systems based on a variety of criteria. This study reports that the cell type involved is also distinct, as determined by phenotypic characteristics. The LAK effector cell phenotype was analyzed in parallel with alloimmune CTL, and LAK were found to be similarly susceptible to the monoclonal anti-T cell antibodies OKT-3 or OKT-8 plus complement. In contrast the LAK precursor was not susceptible to the OKT-3 or Leu-1 antibodies plus complement, while the ability to generate alloimmune CTL was totally obliterated when tested using the same PBL responder population; in fact, generation of LAK was found to be augmented five- to sixfold, clearly suggesting that LAK precursor cells are not T lymphocytes as defined by these antibodies. LAK precursors were found to be abundant in NK cell-enriched Percoll gradient fractions, which had been depleted of the 29 degrees C E- rosetting "high affinity" T cells. However, LAK precursors were found to be distinct from the majority of NK cells since lysis of fresh PBL with the monoclonal antibodies OKM-1, Leu-7, or OKT-11 significantly depleted or totally eliminated NK activity, while subsequent activation of the remaining cells generated high levels of LAK and in some cases augmented levels of LAK. LAK precursors were found to be distributed in the thymus, bone marrow, spleen, lymph node, and thoracic duct in addition to the PBL. Therefore, while the cell(s) responsible for activation and expression of LAK activity have some common features with the classic T cell-mediated CTL and NK cell systems, the LAK precursor cells are clearly distinct as determined by phenotype analysis using monoclonal antibodies and complement, and at present must be classified as a "null" cell.

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