fc gamma receptor cancer adcc

PURPOSE: Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin's lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro...

PURPOSE: The anti-HER-2/neu monoclonal antibody trastuzumab has been shown to engage both activatory (fragment C receptor [Fc gamma R]IIIa; Fc gamma RIIa) and inhibitory (Fc gamma RIIb) antibody receptors and Fc gamma R polymorphisms have been identified that may affect the antibody-dependent cell-mediated cytotoxicity (ADCC) of natural-killer cells/monocytes. In this study, we tested whether Fc gamma R polymorphisms are associated with clinical outcome of patients with breast cancer who received trastuzumab...

V gamma 9 V delta 2 T cells exert potent cytotoxicity toward various tumor cells and adoptive transfer of V gamma 9 V delta 2 T cells is an attractive proposition for cell based immunotherapy. V gamma 9 V delta 2 T cells expanded in the presence of Zoledronate and IL-2 express CD16 (Fc gamma RIII), which raises the possibility that V gamma 9 V delta 2 T cells could be used in conjunction with tumor targeting monoclonal antibody drugs to increase antitumor cytotoxicity by antibody dependent cellular cytotoxicity (ADCC)...

Preliminary results from a pilot trial on trastuzumab's mechanism of action against operable breast tumors overexpressing Her2 suggested a role for antibody-dependent cell cytotoxicity (ADCC). To examine factors affecting ADCC intensity and variability, we extended this study to the phenotypic and functional analysis of circulating mononuclear cells in 18 patients. ADCC was induced by trastuzumab therapy in 15 of 18 patients (83%). Inability to develop ADCC in three patients did not depend on inadequate levels of trastuzumab because further increase in its concentration in vitro was ineffective...

PURPOSE: Cetuximab, a chimeric immunoglobulin G 1 (IgG1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), has shown efficacy in 10% of patients with metastatic colorectal cancer (CRC). Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the modes of action for rituximab and trastuzumab. Fragment c (Fc) portion of IgG1 mAb has shown to induce ADCC. Fragment c gamma receptors (FcgammaR) play an important role in initiating ADCC...

Simian virus 40 (SV40) large tumor antigen (Tag) represents a virus-encoded tumor-specific antigen expressed in many types of human cancers and a potential immunologic target for antitumor responses. Fc receptors are important mediators in the regulation and execution of host effector mechanisms against conditions including infectious diseases, autoimmunity, and cancer. By examining tumor protection in SV40 Tag-immunized wild-type BALB/c mice using an experimental pulmonary metastasis model, we attempted to address whether engagement of the immunoglobulin G Fc receptors (FcgammaRs) on effector cells is necessary to mediate antitumor responses...

Antibody-dependent cellular cytotoxicity (ADCC) is one of the mechanisms of tumor killing during antibody (Ab) immunotherapy, and a role for myeloid cells as effectors has been observed in several models. We are developing immunotherapy approaches based on administration of large numbers of ex vivo interferon-gamma-activated macrophages to cancer patients. With a quantitative assay measuring killing of nonproliferating tumor cells, we evaluated whether, in physiologic conditions, these macrophages synergize with the anti-CD20 Ab rituximab for killing primary B-cell chronic lymphocytic leukemia (B-CLL) cells...

A phase I study of the bispecific antibody MDX-H210 in combination with granulocyte colony-stimulating factor (G-CSF) was performed in stage IV breast carcinoma patients, overexpressing HER-2/neu. MDX-H210, constructed by crosslinking antigen binding fragments (F(ab') fragments) of monoclonal antibody (mAb) H22 to Fc gamma receptor I (FcgammaRI), and mAb 520C9 to HER-2/neu, respectively, mediates the lysis of tumour cells in vitro, and in human FcgammaRI transgenic mouse models. The proto-oncogene HER-2/neu is overexpressed in approximately 30% of breast cancer patients, and represents a promising target for antibody-based immunotherapy...

Clinical use of Herceptin (trastuzumab), which is a humanized monoclonal antibody against HER2, started for patients with HER2-overexpressing breast cancer. To potentiate the efficacy of the Herceptin therapy, this study focused on the combination of Herceptin with activated immune lymphocytes. We used peripheral blood mononuclear cells (PBMCs) as effector cells and used HER2-unexpressing K562 cells, HER2-weakly-expressing breast carcinoma cells (Breast-M), or HER2-strongly-expressing breast carcinoma cells (BT-474) as target cells...

Immunostimulatory CpG oligodeoxynucleotides (ODNs) can enhance the therapeutic effect of monoclonal antibodies (mAbs) by enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). Distinct classes of CpG ODNs have been found recently to stimulate different effector cell populations. We used murine cancer models to explore the role of various effector cell populations in the antitumor activity seen with mAbs combined with CpG ODNs of the A and B classes. In the 38C13 syngeneic murine lymphoma model, both CpG A and CpG B enhanced the efficacy of murine antilymphoma mAb...

The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20% of breast adenocarcinomas and is recognized by a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody-dependent cell cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (FcgammaRIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin-2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2...

Human epithelial mucin, MUC-1, is commonly expressed in adenocarcinoma including 80% of breast cancers. erbB-2 is overexpressed in approximately 30% of breast cancers. Expression of MUC-1 and erbB-2 may be partially overlapping but discoordinate. Therefore, combined use of antibodies directed against these two antigens might increase the number of patients who benefit from immunotherapy. Monoclonal antibody (MAb) DF3 recognizes the MUC-1 tandem repeat. We investigated phagocytosis and cytolysis of cultured human breast cancer cells by monocyte-derived macrophages mediated by MAb DF3 and its bispecific antibody (BsAb) DF3xH22 with the second epitope directed against the Fc component of phagocytic cells...

The first monoclonal antibodies (mAbs) approved for cancer therapy are now in Phase II and III trials, but the critical mechanism(s) determining efficacy and response in patients are still largely undefined. Both the direct antigen-binding (Fab) and constant (Fc) regions of mAbs can contribute to their biological activity. However, Clynes et al (Nat Med 2000, 6:443) recently suggested that the latter (at least in experimental models) might be the dominant component in vivo, triggering host responses to destroy cancer cells...

Stimulation of monocytes by interaction of monoclonal antibodies (mAbs) with Fc gamma receptors (FcgammaRs) results in the activation of various monocyte effector functions. In the present investigation we show that the anti-Lewis Y (LeY) anti-tumour mAb ABL 364 and its mouse/human IgG1 chimaera induce both antibody-dependent cellular cytotoxicity (ADCC) and the release of tumour necrosis factor alpha (TNF-alpha) during mixed culture of monocytes with LeY+ SKBR5 breast cancer cells in vitro. Although anti-LeY mAb-mediated TNF-alpha release paralleled ADCC activity, cytokine release required a higher concentration of sensitizing mAb than the induction of cytolysis...

Immunotherapies directed to the proto-oncogene product HER-2/neu, which is overexpressed on a subset of breast and other carcinomas, currently receive considerable attention. We have investigated cell-mediated effector mechanisms of HER-2/neu antibodies against breast cancer cell lines. Compared to unfractionated control blood, whole blood from patients during granulocyte colony-stimulating factor (G-CSF) treatment exhibits significantly enhanced lysis (P < 0.001) of SK-BR-3 cells in the presence of HER-2/neu antibody 520C9...

The effect of tumor necrosis factor (TNF) and interferon (IFN)-gamma on antibody-dependent cellular cytotoxicity (ADCC) in patients with ulcerative colitis (UC) was investigated. ADCC activity was measured by the 51Cr release assay, using peripheral blood mononuclear cells of healthy subjects as effector cells and RPMI 4788 cells derived from human colon cancer as target cells. ADCC activity under sera from healty subjects remained low whether or not the effector cells were pretreated with TNF (100 U/ml, 16h)...

Human intestinal intraepithelial lymphocytes (IEL) demonstrate target cell-restricted spontaneous cytotoxic (SC) activity that is due to CD2+CD3+CD8+CD16-CD56- effector cells; they kill epithelial cell (EC) tumours (such as DLD-1 colon cancer cells), but not natural killer (NK)-sensitive K-562 cells. The present study shows that the measured levels of SC activities by IEL correlated with those of autologous lamina propria lymphocytes (LPL), but not with those of peripheral blood lymphocytes (PBL). Also, the susceptibilities of DLD-1 cell clones to lysis by IEL and PBL effector cells did not correlate, suggesting different mechanisms of lysis...

To clarify the contribution of ADCC and NK activities to host immune response against cancer, the characteristics of cells mediating these activities were examined in the peripheral blood lymphocytes of normal volunteers, and the changes of these activities were also evaluated in patients with lung cancer and metastatic pulmonary tumors before and after chemotherapy. OAT cells derived from small cell carcinoma of the lung and K-562 cells derived from erythroleukemia were used as target cells of ADCC and/or NK assay...

Sixteen untreated patients with squamous cell carcinoma of the oral cavity were tested for in vitro immune status in comparison with the normal healthy donors. The parameters investigated were total leukocyte and lymphocyte counts, percentages and absolute counts of T- and B-cells in circulation, subsets of T-cells identified by the Fc receptors, phytohemagglutinin (PHA), and mixed lymphocyte culture (MLC) responses, natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) activities, and circulating immune complexes (CICs)...

Chimeric antibodies were constructed in which the murine variable region of anti-colorectal cancer monoclonal antibody CO17-1A was joined with human gamma 1, gamma 2, gamma 3, and gamma 4 constant regions. Human-mouse chimeric proteins were compared with the parental murine IgG2a antibody CO17-1A for their ability to participate in tumor-cell destruction by human and murine effector cells in antibody-dependent cell-mediated cytotoxicity (ADCC) assays. All of the chimeric antibodies showed different degrees of ADCC with human lymphocytes, monocytes, and granulocytes and with murine macrophages...