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The transmembrane protein receptor CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily and is involved in costimulation of immune cells. CD40 is expressed by antigen-presenting cells (APCs) including dendritic cells (DCs), macrophages, B-cells, and monocytes but is also expressed on other cell types such as endothelial cells, epithelial cells, and platelets and CD40 expression has been demonstrated on multiple tumor cells, including B cell lymphoma and renal cancer cells. Initial studies using an agonist CD40 antibody showed increased cytotoxic lymphocyte (CTL) responses against poorly activating tumor antigens and promoted the effector function of cytotoxic T cells tolerized by tumor antigens. Therefore, targeting CD40 with monoclonal antibodies has potent anti-tumor efficacy.
Figure 1. CD40 in regulating anti-tumor T cell responses. (Moran A E, et al. 2013)
The CD40 as Targets for Cancer Immunotherapy
Physiologically, signaling through CD40 on APC is thought to represent a major component of T-cell help and mediates, to a large extent, the capacity of helper T cells to license APC. Ligation of CD40 on DC, for instance, induces increased surface expression of costimulatory and MHC molecules, production of proinflammatory cytokines, and enhanced T-cell triggering. CD40 ligation on resting B cells facilitates antigen-presenting function and proliferation. The consequences of CD40 signaling are multifaceted and rely on the type of cell expressing CD40 and the microenvironment in which the CD40 signal is provided. Like some other TNF receptors, CD40 signaling is mediated by adapter molecules rather than by inherent signal transduction activity of the CD40 cytoplasmic tail. Downstream kinases are activated when the receptor assembled, multicomponent signaling complex translocates from CD40 to the cytosol and many well-characterized signal transduction pathways are activated. In preclinical models, rat anti-mouse CD40 mAb show remarkable therapeutic activity in the treatment of CD40þ B-cell lymphomas and are also effective in various CD40-negative tumors. These mAb are able to clear bulk tumors from mice with near terminal diseases.
Targeting CD40 with an agonist mAb has been tested in patients with both solid tumors and hematological cancers. The therapeutic anti-human CD40 mAbs Lucatumumab and Dacetuzumab are recombinant antibodies and have become the leading drug candidates in relation to antiCD40 based immunotherapy. Lucatumumab is a fully-humanized antagonistic antibody against CD40 and exerts its primary function through opsonization followed by antibody-dependent cell-mediated cytotoxicity (ADCC). Dacetuzumab is a humanized anti-CD40 agonistic mAb which triggers CD40-mediated signaling in various cells. Administration of anti-CD40 mAb is most commonly systemically, e.g. by i.v. administration, but in some cases injection directly into the tumor has been tested and may lead to a better therapeutic response. It has been postulated, that a part of this beneficial effect is due to a slow release of the mAb which may prolong access for effector cells and in the meantime reduce antibody-mediated side-effects and toxicity.
CD40 Gene Editing Service
CRISPR/Cas9 PlatformCB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control CD40 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.
|Service||Details||Alternative cell lines or animal species|
|CD40 Gene Editing Cell Line Generation||HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.|
|CD40 Gene Editing Animal Model Generation||Mouse, rat, rabbit, zebrafish, C. elegans, etc.|
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