Preferred Label : SIRPa-Fc-CD40L Fusion Protein SL-172154;
NCIt synonyms : CD172a-Fc-CD40L Chimeric Protein SL-172154; SIRPa-Fc-CD40L SL-172154;
NCIt definition : A bi-functional fusion protein consisting of the extracellular domains (ECDs) of human
signal-regulatory protein alpha (SIRPalpha; SIRPa; CD172a) and CD40 ligand (CD40L;
CD154; TRAP; TNFSF5) linked via a human Fc domain, with potential immune checkpoint
inhibitory and antineoplastic activities. Upon administration, the SIRPa-Fc-CD40L
fusion protein SL-172154 selectively targets and binds to both CD47 expressed on tumor
cells and CD40, a cell surface receptor that belongs to the tumor necrosis factor
(TNF) receptor family, expressed on antigen-presenting cells (APCs). Binding to CD47
blocks the interaction of CD47 with endogenous SIRPa, a cell surface protein expressed
on macrophages. This prevents CD47/SIRPa-mediated signaling and abrogates the CD47/SIRPa-mediated
inhibition of macrophage activation and phagocytosis of cancer cells. This induces
pro-phagocytic signaling mediated by the binding of calreticulin (CRT), which is specifically
expressed on the surface of tumor cells, to low-density lipoprotein (LDL) receptor-related
protein-1 (LRP-1), which is expressed on macrophages, and results in macrophage activation
and the specific phagocytosis of tumor cells. The binding of CD40L to CD40 activates
CD40, increases CD40-mediated signaling and induces proliferation and activation of
B-lymphocytes, shifts the induction of suppressive macrophages towards immunostimulatory
macrophages, activates monocyte-derived dendritic cells (moDCs), and leads to the
secretion of inflammatory cytokines. This activates the immune system to induce the
proliferation and activation of cytotoxic T-lymphocytes (CTLs) against tumor cells.
The crosslinking specifically enhances antigen presentation to CD8 and CD4 T lymphocytes
and tumor cell phagocytosis by the APC. CD47, also called integrin-associated protein
(IAP), is a tumor-associated antigen (TAA) expressed on normal, healthy hematopoietic
stem cells (HSC) and overexpressed on the surface of a variety of cancer cells. Expression
of CD47, and its interaction with SIRPa, leads to the inhibition of macrophage activation
and protects cancer cells from phagocytosis, thereby allowing cancer cells to proliferate.;
Molecule name : SL 172154; SL-172154;
NCI Metathesaurus CUI : CL1407529;
Origin ID : C173706;
UMLS CUI : C5418018;
Semantic type(s)
- concept_is_in_subset
- has_target
