CAMBRIDGE, Mass.—Codiak BioSciences, Inc. has announced the first preclinical data for its engEx platform program, exoASO. These data, which were presented at the American Association for Cancer Research’s Special Conference on Tumor Immunology and Immunotherapy, demonstrate the potential of engineered exosomes incorporating an antisense oligonucleotide (ASO) to selectively reprogram tumor-associated macrophages and generate potent anti-tumor activity.
Highly immunosuppressive macrophages (M2 phenotype) are potent drivers of tumor growth which create an immunosuppressive environment in the tumor. Codiak, using its proprietary engEx platform, developed engineered exosomes exogenously loaded with an ASO as part of its exoASO program. exoASO is designed to selectively deliver ASOs to M2 macrophages, targeting and decreasing the expression of the key immunosuppressive transcription factors STAT6 and C/EBPβ.
“We continue to expand the therapeutic potential of engEx engineered exosomes and build our pipeline of novel biologics designed to target pathways that have been historically difficult to effectively or safely drug. These data show us the utility of exoASO in both selectively targeting classically undruggable transcription factors and successfully reprogramming immunosuppressive macrophages, representing a potentially groundbreaking approach,” said Douglas E. Williams, Ph.D., president and chief executive officer of Codiak.
Key conclusions from both in vitro and in vivo preclinical studies demonstrate that exoASO effectively reprogrammed M2 macrophages to a pro-inflammatory M1 phenotype, promoting targeted anti-tumor activity. In vitro, exoASO was preferentially taken up by M2 macrophages to a significantly greater extent than free ASO, resulting in greater knockdown of STAT6 and C/EBPβ mRNA. Subsequent gene expression analysis and cytokine assays showed an up to 40-fold increase in TNFα and an up to 29-fold decrease in IL-10 associated with exoASO treatment, consistent with repolarization from immunosuppressive M2 macrophages to immune stimulatory M1 macrophages.
In in vivo studies using a PD1-refractory mouse tumor model, both exoASO-STAT6 and exoASO-C/EBPβ showed significant anti-tumor growth inhibition as monotherapies, resulting in 50 percent and 60 percent complete responses, respectively, compared to no complete responses with free ASO. mRNA analysis of tumor samples examining expression of M2 and M1 cytokines was consistent with reprogrammed macrophages from the M2 to M1 phenotype.
Data from the poster, entitled “Reprogramming of tumor-associated M2 macrophages with antisense oligonucleotides-loaded exosomes results in potent single-agent antitumor activity,” is available for download here.