Abstract 2445: Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models
ABSTRACT Alemtuzumab is a recombinant humanized IgG1 monoclonal antibody directed against CD52, an antigen expressed on the surface of normal and malignant B and T lymphocytes. Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but the exact mechanism by which the antibody depletes malignant lymphocytes in vivo is not clearly defined. To address this issue, the anti-tumor activity of alemtuzumab was studied in disseminated and subcutaneous xenograft tumor models. The density of CD52 target antigen on the surface of tumor cells appeared to correlate with the anti-tumor activity of alemtuzumab. Deglycosylation of alemtuzumab resulted in a loss of cytotoxicity in vitro and was found to abolish anti-tumor activity in vivo. Individual inactivation of effector mechanisms in tumor-bearing mice indicated that the protective activity of alemtuzumab in vivo was primarily dependent on ADCC mediated by neutrophils and to a lesser extent NK cells. Increasing the number of circulating neutrophils by treatment with G-CSF enhanced the anti-tumor activity of the antibody, thus providing further evidence for the involvement of neutrophils as effector cells in the activity of alemtuzumab.
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ABSTRACT: Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions'; and the US Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found.British Journal of Pharmacology 12/2011; 166(3):823-46. DOI:10.1111/j.1476-5381.2011.01811.x · 4.99 Impact Factor
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ABSTRACT: The fields of leukemia and lymphoma research have significantly advanced over the recent years as a result of the establishment of cell lines that reflect several aspects of the human disease. These cell lines have been employed in all phases of preclinical research from the immunization of mice to generate new therapeutic antibodies to proof of concept and target validation experiments. In addition, several transgenic mouse or genetically engineered mouse models have been developed that recapitulate many aspects of both leukemia and lymphoma. These models are particularly well suited to the exploration of interactions between tumor and stromal cells and the progression of cancer as it relates to its microenvironment. Therapeutic antibodies including ofatumumab and epratuzumab are currently undergoing clinical trial evaluation based on their activity in models such as these. Xenograft tumor models have been especially instrumental in studies addressing mechanism of action and in evaluating combination therapies. This chapter will primarily explore the use of human cells in xenograft tumor systems as models for evaluating therapeutic approaches. KeywordsLeukemia-Lymphoma-Mouse-Xenograft-Therapeutic12/2010: pages 325-351;
Article: Cancer immunotherapy.[Show abstract] [Hide abstract]
ABSTRACT: Cancer immunotherapy consists of approaches that modify the host immune system, and/or the utilization of components of the immune system, as cancer treatment. During the past 25 years, 17 immunologic products have received regulatory approval based on anticancer activity as single agents and/or in combination with chemotherapy. These include the nonspecific immune stimulants BCG and levamisole; the cytokines interferon-α and interleukin-2; the monoclonal antibodies rituximab, ofatumumab, alemtuzumab, trastuzumab, bevacizumab, cetuximab, and panitumumab; the radiolabeled antibodies Y-90 ibritumomab tiuxetan and I-131 tositumomab; the immunotoxins denileukin diftitox and gemtuzumab ozogamicin; nonmyeloablative allogeneic transplants with donor lymphocyte infusions; and the anti-prostate cancer cell-based therapy sipuleucel-T. All but two of these products are still regularly used to treat various B- and T-cell malignancies, and numerous solid tumors, including breast, lung, colorectal, prostate, melanoma, kidney, glioblastoma, bladder, and head and neck. Positive randomized trials have recently been reported for idiotype vaccines in lymphoma and a peptide vaccine in melanoma. The anti-CTLA-4 monoclonal antibody ipilumumab, which blocks regulatory T-cells, is expected to receive regulatory approval in the near future, based on a randomized trial in melanoma. As the fourth modality of cancer treatment, biotherapy/immunotherapy is an increasingly important component of the anticancer armamentarium.Cancer Biotherapy & Radiopharmaceuticals 02/2011; 26(1):1-64. DOI:10.1089/cbr.2010.0902 · 1.38 Impact Factor