ASO-STAT6-loaded PTGFRN-expressing exosomes CDK-004

A preparation of engineered cell-derived exosomes loaded with an antisense oligonucleotide (ASO) targeting the transcription factor signal transducer and activator of transcription (STAT) 6 (STAT6) on its surface and expressing high levels of the exosome surface glycoprotein prostaglandin F2 receptor negative regulator (PTGFRN; CD315), with potential immunoactivating and antineoplastic activities. Upon intravenous administration, ASO-STAT6-loaded PTGFRN-expressing exosomes CDK004 preferentially targets and binds to antigen-presenting cells (APCs), specifically M2 polarized tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). The selective delivery of ASO STAT6 to the immunosuppressive TAMs with a M2 phenotype allows for selective reduction of STAT6 mRNA expression in these cells. By preventing the STAT6 expression in TAMs, the expression of STAT6 target genes, including the transcription of M2 signature genes, is halted. This increases the expression of M1 genes and leads to the reprogramming of TAMs toward a pro-inflammatory M1 phenotype in the TME, and leads to a cytotoxic T-lymphocyte (CTL)-mediated anti-tumor immune response. This may reduce tumor cell proliferation. STAT6 is a key regulator of the macrophage M2 transcriptional program and represses the activation of the M1 phenotype.