Use of anti-CD3 × anti-HER2/neu bispecific antibody for redirecting cytotoxicity of activated T cells toward HER2/neu+ tumors
ABSTRACT Relapse after adjuvant chemotherapy or high-dose chemotherapy with stem cell transplant for high-risk breast cancer remains high and new strategies that provide additional antitumor effects are needed. This report describes methods to generate highly effective HER2/neu-specific cytotoxic T cells by arming activated T cells with anti-CD3 x anti-HER2/neu bispecific antibody (BsAb). OKT3 and 9184 (anti-HER2) monoclonal antibodies (mAb) were conjugated and used to arm T cells that were subsequently tested in binding, cytotoxicity, and cytokine secretion assays. Armed T cells aggregated and specifically killed HER2/neu(+) breast cancer cells. Cytotoxicity emerged after 6 days of culture, was higher in armed T cells than unarmed T cells at all effector to target ratios (E/T) tested, and increased as the arming dose was increased. At an E/T of 20:1, the mean cytotoxicity of armed activated T cells (ATC) from 10 normal subjects increased by 59 +/- 11% (+/-SD) over that seen in unarmed ATC (p < 0.001) and the mean cytotoxicity of armed ATC from 6 cancer patients increased by 32 +/- 9% above that seen for unarmed ATC (p < 0.0004). After arming, the BsAb persisted on ATC up to 72 h and armed ATC continued to be cytotoxic up to 54 h. The amount of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted was 1699, 922, and 3092 pg/ml/10(6) cells per 24 h, respectively, when armed T cells were exposed to a HER2/neu(+) breast carcinoma cell line. These studies show the feasibility and clinical adaptability of this approach for generating large numbers of anti-HER2-specific, cytotoxic T cells for clinical trials.
- SourceAvailable from: James F Padbury
[Show abstract] [Hide abstract]
- "In order to deliver high numbers of SC to MIs while avoiding the clinical risks of bone marrow harvest or intracardiac injections, we have adapted a new strategy that involves directly targeting SC to the infarct. Borrowing from our experience in retargeting killer T cells to cancer using bispecific antibody (BiAb) technology [Sen et al., 2001], we reasoned that the same strategy could be used to target SC to MIs. "
ABSTRACT: The search for the fountain of youth continues into the 21st century with hopes that embryonic or hematopoietic stem cells (SC) will repair injured tissues in the heart, lungs, pancreas, muscles, nerves, liver, or skin. This commentary focuses on the potential of SC for inducing cardiac regeneration after myocardial injury, the barriers to SC treatment that need to be overcome for ensuring successful cardiac repair, and the experimental approaches that can be applied to the problem.Journal of Cellular Biochemistry 08/2005; 95(5):869-74. DOI:10.1002/jcb.20504 · 3.37 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Bispecific antibodies (BiAbs) offer a means to increase therapeutic efficacy by combining the benefits of two antibodies into one molecule. This property enables the development of therapeutic strategies that are not possible with conventional monoclonal antibodies (mAbs). Advances in antibody engineering and the expanding knowledge of antigen profiling on malignant cells have provided innovative solutions for the development of various formats of BiAbs and their combinations for targeting effector cells to tumor cells. This chapter focuses on the use of BiAbs to redirect non-MHC-restricted ex vivo expanded T cells as a therapeutic platform directed at various tumor-associated antigens in vivo.01/1970: pages 243-271;
- [Show abstract] [Hide abstract]
ABSTRACT: The cell surface receptor for the vitamin folic acid (termed the folate receptor), is often elevated in cancers of the ovary, kidney, lung, mammary gland, brain, endometrium, and myeloid cells of hematopoietic origin. Because the folate receptor (FR) is either absent from normal tissues or localized to the apical surfaces of polarized epithelia, where it is inaccessible to circulating drugs, folate-linked drugs do not normally accumulate in healthy tissues. However, since the same receptor is fully accessible on cancer cells, it has frequently been exploited as a target for receptor-directed cancer therapies, including chemotherapies and immunotherapies. In fact, most strategies for the immunotherapy of cancer have at some time been adapted to treat FR-expressing tumors. In this article, recent progress in the retargeting of the immune system to folate receptor-expressing cancers is summarized and future strategies for redirecting natural killer cells, antibodies and cytotoxic T lymphocytes to this large class of malignancies are proposed.Journal of Controlled Release 09/2003; 91(1-2):17-29. DOI:10.1016/S0168-3659(03)00215-3 · 7.26 Impact Factor