On November 18, 2019 Codiak BioSciences, Inc., a company at the forefront of advancing engineered exosomes as a new class of biologic medicines, reported the first preclinical data for its engEx Platform program, exoASO. These data, which were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)’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 (Press release, Codiak Biosciences, NOV 18, 2019, View Source [SID1234551438]).
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"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," said Douglas E. Williams, Ph.D., President and Chief Executive Officer of Codiak. "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."
Highly immunosuppressive macrophages (M2 phenotype) are immune cells that are potent drivers of tumor growth by creating an immunesuppressive environment in the tumor. Utilizing its proprietary engEx Platform, Codiak 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.
Key conclusions from 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 titled "Reprogramming of tumor-associated M2 macrophages with antisense oligonucleotides-loaded exosomes results in potent single-agent antitumor activity" (A50) is available for download on the Codiak website.
About engEx Platform
The engEx Platform is Codiak’s proprietary exosome therapeutic engine for engineering and manufacturing novel exosome product candidates designed to target multiple pathways throughout the body. Using this platform, Codiak can design exosomes with precisely engineered properties, incorporate various types of biologically active molecules and direct them to specific cell types and tissues. These exosomes engage by cellular uptake, membrane-to-membrane interaction or a combination of both, and are designed to change the biological functioning of the recipient cells in order to produce the intended therapeutic effect. Codiak is building a broad pipeline of engEx product candidates that may have a transformative impact on the treatment of many diseases.