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Developed via Codiak’s proprietary engEx Platform, exoASO-STAT6 is surface-loaded with an antisense oligonucleotide (ASO) targeting the STAT6 transcription factor. Transcription factors such as STAT6 that regulate gene families are ideal targets for potent repolarizing of tumor-associated macrophages, yet they have been very challenging to drug with common drug modalities. We have designed exoASO-STAT6 to allow for the necessary delivery specificity of the STAT6 ASO to the M2 macrophages to selectively repolarize these cells, resulting in strong pre-clinical single agent anti-tumor activity not possible with free ASO and not observed with other pathway indicators. Our preclinical studies with exoASO-STAT6 showed preferential uptake into M2 polarized macrophages, increased selective delivery, and potency compared to free ASO and potent reduction in STAT6 mRNA, which led to a distinct decrease in expression of M2 genes and increase in expression of M1 genes.

We are developing intravenously-administered exoASO-STAT6 for various myeloid rich cancers, including hepatocellular carcinoma, pancreatic ductal adenocarcinoma, colorectal cancer, lung adenocarcinoma, uveal melanoma, glioma, thyroid cancer, and ovarian cancer.

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exoASO-STAT6: Displays in vivo STAT-6 Knockdown, TAM Reprograming, and Single Agent Activity

Chart exo ESO STAT 1 mobile
Chart exo ESO STAT 2 mobile
Intra-tumoral administration with a scrambled ASO, free STAT6 ASO and exoASO-STAT6. exoASO-STAT6 led to selective knockdown of STAT6 in myeloid cells, down regulation of the M2 marker CSF1R and up regulation of the M1 marker, NOS2.
Chart exo ESO STAT 3 mobile
As a single agent, exoASO STAT6 resulted in complete tumor remissions (CRs) in 50% of mice; CRs were not observed in any other control groups.
Chart exo ESO STAT 1 desktop
Intra-tumoral administration with a scrambled ASO, free STAT6 ASO and exoASO-STAT6. exoASO-STAT6 led to selective knockdown of STAT6 in myeloid cells, down regulation of the M2 marker CSF1R and up regulation of the M1 marker, NOS2.
Chart exo ESO STAT 2 desktop
As a single agent, exoASO STAT6 resulted in complete tumor remissions (CRs) in 50% of mice; CRs were not observed in any other control groups.