Chimeric antigen receptor

Kalos M, Levine BL, Porte- DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011 3(95) 95ra73. doi 10.1126/ scitranslmed.3002842. 

Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoc5dic leukemia. N Engl J Med. 2011 365 725-33. 

Basiliximab is a chimeric mouse-human monoclonal antibody to the IL-2Ra receptor of T cells and daclizumab (Zenapax) is a humanized monoclonal antibody against the same receptor. They prevent binding of interleukin-2 to the CD25 antigen on activated T-lymphocytes thus inhibiting T-lymphocyte proliferation. Like the similar drug basiliximab, daclizumab reduces the incidence and severity of acute rejection in kidney transplantation without increasing the incidence of opportunistic infections. 

Chimeric murine monoclonal antibody reacts with the CD25 antigen on T cells, inhibiting the binding of interleukin-2 (IL-2) to its receptor (IL-2R)-appears to bind only to activated T lymphocytes and to monocytes macrophages... 

Monoclonal antibodies can vary tremendously in terms of isotype, construction (animal derived, chimeric, humanized, bound to toxin), ability to activate complement, binding avidity, target specificity, and whether it binds and blocks or binds and activates the receptor. Monoclonal antibodies may be directed toward soluble or membrane bound receptors or receptor ligands, tumor antigens, growth factor or their receptors. Therefore toxicity and side effects are equally variable [68]. 

By contrast, GPI-anchored proteins are poorly represented in elathim coated pits [158], the main pathway for receptor-mediated endocytosis. The cytoplasmic tail of most cell suiface receptors mediates their entry into coated pits where they are subsequently internalized and degraded or recycled (reviewed in ref. [159]). The lack of a cytoplasmic tail may preclude GPI anchors from entering coated pits, resulting in an inereased resident time on the cell surface. Ninety percent of lymphoma Thy-1 is at the cell surface and has a turnover rate an order of magnitude slower than the transmembrane H-2 antigen in the same cells [158]. Internalization rates of chimeric GPI-anchored proteins transfected into MDCK cells can be as low as 2% of the internalization rate for the entire cell surface [160]. 

In almost 40% of HL patients, H/RSCs express EBV-associated antigens. EBV-specihc cytotoxic T lymphocytes expressing the anti-CD30 artificial chimeric T-cell receptor have been employed for immunotherapy of HL. Adoptive transfer of EBV-specific cytotoxic T lymphocytes (EBV-CTLs) have shown that these cells persist in patients with HL to produce complete tumor responses.Treatment failure occurs if a subpopulation of malignant cells lacks or loses expression of EBV antigens. To overcome this limitation, investigators have prepared EBV-CTLs that retained antitumor... 

Chimeric antibodies are hybrid molecules combining the antigen-specific variable domain of the mouse antibody fused to the constant regions of a human IgG molecule (Fig. 1.4). This reduces the risk of immunogenicity somewhat, and the human Fc domain prolongs the serum half-life and is more effective in triggering the effector systems of complement and Fc receptors. 

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