CD248 Gene Editing

Endosialin/CD248/TEM1, a transmembrane glycoprotein expressed on fibroblasts and pericytes during tissue development and present in the adult in several mesenchymal cell types, is associated with inflammation and tumor neovascularization. CD248 can be useful as a molecular marker and therapeutic target for sarcoma and other diseases. Originally recognized as the antigen of an antibody raised in mice against human fetal fibroblasts (FB5), CD248 was found to be expressed by human solid tumor vasculature and was detected in a subset of cells enriched for endothelium through selection with P1H12, an anti-CD146 antibody, from a colorectal tumor specimen. CD248 is now regarded as a mesenchymal marker, expressed on various fibroblast types, pericytes, smooth muscle cells, mesenchymal stem cells and osteoblasts. CD248 is also involved in the regulation of the proliferation of mesenchymal elements.

CD248 and Fibrotic Diseases

CD248 is an activation marker of mesenchymal lineage cells including tumor-associated pericytes, activated vascular smooth muscle cells (VSMC), and stromal myofibroblasts. Synovial tissue biopsy samples from healthy tissue, from rheumatoid arthritis, and from psoriatic arthritis showed that synovium from psoriatic arthritis and rheumatoid arthritis and from mice after the induction of collagen antibody-induced arthritis stained strongly for CD248 in perivascular and fibroblast-like stromal cells. Studies indicated that CD248 may be involved in synovial hyperplasia and leukocyte accumulation in inflammatory arthritis.

In normal renal tissue, CD248 was expressed by pericytes, and occasional stromal fibroblasts. CD248 was expressed by α-SMA-stromal cells and α-SMA-myofibroblasts but not CD45+ leukocytes. Therefore, CD248 defines a subset of myofibroblasts linked to albuminuria and tubulointerstitial damage during tissue remodeling in chronic kidney disease. Tissue fibrosis and microvascular rarefaction are markers of progressive renal disease. In standard renal fibrosis models, CD248 knockout mice were protected from fibrosis and microvascular rarefaction owing to a stabilizing effect of pericytes with less migration and differentiation of pericytes toward a myofibroblast phenotype. Therefore, CD248 stromal cells have a role in renal fibrosis. Moreover, targeting CD248 was effective at inhibiting both microvascular rarefaction and renal fibrosis through modulation of pericyte and stromal cell function.

CD248 and Cancer Therapy

CD248 is widely expressed during embryonic development and is silenced in normal adult tissues but is re-expressed in solid tumours, including sarcomas, melanomas and a broad range of carcinomas. CD248 overexpression has been associated with aggressive tumour behaviour and poor patient prognosis. It is related to tumour-cell vascular adhesion and migration, neoangiogenesis, local invasion and metastasis. In cancer tissues, CD248 protein was detected in tumor capillaries and fibroblasts. CD248 stained NG2-positive cells, i.e., pericytes with subcellular localization of CD248 on the surface of the pericyte cell-body and finger-like processes. Notably, although CD248 knockout mice exhibit no obvious phenotype and normal wound healing, compared with wild-type mice, transplanted tumours grow more slowly, are less invasive and develop fewer metastases in CD248 knockout mice, indicating that host CD248-positive stroma promotes malignancy.

Pre-clinical studies suggest that CD248 is a safe and promising target for cancer therapy. Recent studies propose several methods including tumor immune-PET applications, endosialin-specific DNA vaccination targeting tumor vasculature, and cytotoxic immunotherapy with anti-endosialin humanized antibody ontuxizumab (MORAb-004) or with antibody-drug conjugate. MORAb-004, a humanised mAb derived from FB5, is used to neutralize TEM1. Although the efforts towards clinical applications are only in the early stage of pre-clinical and/or clinical development, they show good antitumor activity, good safety profile and pharmacokinetics. CD248 is undoubtedly worthy of further study to build a rationale for its effective anti-cancer therapeutic targeting.