The other side of the coin is that CD47 is a universal marker of self in normal healthy tissue, regulating programmed cell removal by homeostatic phagocytosis

jamha December 10, 2024 0 Comments

The other side of the coin is that CD47 is a universal marker of self in normal healthy tissue, regulating programmed cell removal by homeostatic phagocytosis. Such a bispecific design could be applied to limit the extent of neutralization of other ubiquitously expressed therapeutic targets. Keywords: bispecific antibody, TNFSF13 cancer immunotherapy, pharmacokinetics, phagocytosis, macrophage, immune checkpoint, CD47, CD19, mesothelin Graphical Abstract Open in a separate window CD47 is a widely expressed anti-phagocytic dont eat me signal. Cancer cells upregulate CD47 expression to escape phagocytic clearance and immune surveillance. Dheilly et?al. show how bispecific antibodies can be used as an efficient and safe means for therapeutic targeting of CD47 in cancer. Introduction Recent clinical success of monoclonal antibodies targeting T?cell checkpoint pathways has spawned unprecedented enthusiasm about cancer immunotherapy as an effective means of curing cancer or, at least, taming cancer to transform it into a chronic illness.1, 2 However, the final success of immunotherapy will ultimately depend on combined mobilization of multiple arms of the Mitragynine immune system, including innate immune cells that sit at the interface between cancer and its microenvironment, and act both as effectors and coordinators of anti-tumor and tumor-promoting immune responses.3, 4, 5, 6 Mononuclear phagocytes, such as macrophages, are key players shaping the immune environment of the tumor. Not surprisingly, cancer cells have evolved mechanisms to evade recognition and immune attack by these cells. A commonly used stratagem is to hijack CD47, a ubiquitous innate immune checkpoint receptor used to control homeostatic phagocytosis.7, 8, 9, 10 CD47 inhibits phagocytosis by engaging signal regulatory protein alpha (SIRP) on the effector cell, which induces a de-phosphorylation cascade paralyzing the acto-myosin machinery needed for the engulfment process.7, 8, 11 The dont eat me signal conveyed by the CD47-SIRP interaction efficiently offsets potent eat me signals from phagocytosis-activating receptors such as Fc-gamma receptors, complement receptors, or low-density lipoprotein receptor-related protein 1 (LRP1).12, 13 Cancer cells upregulating CD47 trick the immune system to prevent Mitragynine it from mounting effective antitumor responses.9, 10, 14 CD47 is overexpressed on a majority of hematological and solid tumors, with particularly high levels on cancer stem cells (CSCs),9, 15, 16, 17, 18, 19 and high CD47 levels are generally correlated with poor survival.9, 10, 17, 19, 20, 21, 22, 23, 24 In preclinical experiments, CD47 blockade increased phagocytosis of tumor cells in?vitro and potentiated anti-tumor therapies in numerous human xenograft models.9, 10, 20, 21, 23, 24, 25, 26, 27, 28 In?addition to stimulating cancer cell phagocytosis, CD47 blockade was shown to support other anti-tumor mechanisms, such as enhancement of antibody-dependent cell-mediated cytotoxicity (ADCC),26 direct induction of apoptosis of cancer cells by CD47 cross-linking,18, 29, 30, 31 induction of differentiation of CSCs, and inhibition of tumorigenicity.19, 28, 32, 33 CD47 neutralization was also recently?shown to promote the development of anti-tumor adaptive T?cell responses,34, 35, 36, 37 possibly as a Mitragynine consequence of increased tumor cell uptake by professional antigen-presenting cells and Mitragynine enhanced antigen cross-presentation.14, 38 Hence, there is a strong rationale for therapeutic targeting of CD47, and numerous strategies are currently being pursued toward this goal. The most advanced are two anti-CD47 blocking monoclonal antibodies and a receptor fusion protein (SIRP-Fc) that recently entered human trials (“type”:”clinical-trial”,”attrs”:”text”:”NCT02678338″,”term_id”:”NCT02678338″NCT02678338, “type”:”clinical-trial”,”attrs”:”text”:”NCT02641002″,”term_id”:”NCT02641002″NCT02641002, “type”:”clinical-trial”,”attrs”:”text”:”NCT02367196″,”term_id”:”NCT02367196″NCT02367196, and “type”:”clinical-trial”,”attrs”:”text”:”NCT02663518″,”term_id”:”NCT02663518″NCT02663518). However, because CD47 is ubiquitously expressed, the efficacy and the safety of these CD47 blocking strategies may be negatively affected by a large antigen sink represented by heathy cells.39 A proposed solution is to target the receptor of CD47 instead (i.e., SIRP), which has a more restricted expression pattern.26, 40 Yet another alternative would be to use dual-targeting bispecific antibodies (biAbs) with the aim of limiting CD47 neutralization to cancer cells. Because of physical association of two antibody arms with different antigen specificities, biAbs offer new mechanisms of action, Mitragynine not supported by traditional monoclonal antibodies (mAbs) or antibody mixes, paving the way to new therapeutic opportunities.41, 42, 43 For instance, dual-targeting biAbs can concurrently engage two different antigens on the cell.