Development Update – Codiak’s engEx platform for engineered exosomes and therapeutic potential of exoSTING

• In vitro and in vivo profile of exoSTING showed greater potency, preservation of T cells and APCs, greater systemic tumor antigen specific immune response, reduced systemic cytokine production, and enhanced anti-tumor immunity compared to free STING agonist
• Codiak’s PTGFRN protein scaffold enables efficient, high-density surface display of diverse therapeutic proteins and enhanced anti-tumor activity in preclinical models

Codiak BioSciences, a leading exosome therapeutics company, today presented data supporting the therapeutic potential of the engEx^TM Platform for engineering exosomes and its exoSTING product candidate as highlighted at the 2019 American Association for Cancer Research (AACR) Annual Meeting, held March 31 through April 3 in Atlanta, Georgia. Using its engEx Platform, Codiak engineers exosomes — natural intercellular messengers — to have precise and intentionally chosen properties, to incorporate various types of biologically active molecules, and to be directed to specific cell types and tissues. exoSTING is Codiak’s precision engineered exosome therapeutic candidate loaded with a potent small molecule STING (stimulator of interferon genes) agonist. Codiak is conducting IND-enabling studies of exoSTING and plans to begin a Phase 1/2 trial in the immuno-oncology setting during the first half of 2020.

exoSTING

exoSTING is one of Codiak’s lead exosome therapeutic candidates that specifically targets the STING pathway in antigen presenting cells (APCs). exoSTING has been evaluated in a variety of preclinical studies including syngeneic tumor models refractory to checkpoint therapy, the results of which were featured in a presentation during the meeting’s Cancer Vaccines and Intratumoral Immunomodulation Minisymposium. Key conclusions from the preclinical analysis highlight the unique profile of exoSTING to selectively activate the STING pathway in tumor-resident APCs, resulting in systemic anti-tumor immunity without toxic systemic cytokine elevation:

• exoSTING demonstrated enhanced potency and selective activation in human peripheral blood mononuclear cells (PBMCs), including monocytes and myeloid dendritic cells, compared to free STING agonist.
• Exosomes loaded with the novel exosome surface glycoprotein prostaglandin F2 receptor negative regulator (PTGFRN, formerly designated Protein X) demonstrated enhanced APC activation and improved potency in a B16F10 tumor model as compared to the free STING agonist.
• When delivered intratumorally, exoSTING displayed tumor retained pharmacology, with enhanced anti-tumoral effect and reduced systemic inflammatory cytokine production compared to optimal doses of free STING.
• exoSTING preserved tumor resident T-cells and APCs to induce better tumor antigen specific immune response.
• exoSTING improved anti-tumor immunity compared to free STING agonist in primary subcutaneous B16F10 tumors as well as non-primary distant (lung) tumors, where complete responses were histologically confirmed. Complete responses were not seen with free STING.
• This anti-tumor immunity mediated by exoSTING is dependent on CD8 T-cells.

engEx Platform

The potential of the engEx Platform to generate novel exosome therapeutic candidates was characterized in a poster during the Novel Screening and Delivery Technologies Session at AACR. With the engEx Platform, Codiak aims to functionalize the surface of its engineered exosomes with proteins and peptides– an important strategy to harness their therapeutic potential. Comparative proteomic analysis of stringently purified exosomes led to the identification of several highly enriched and unique proteins, including PTGFRN. Codiak has developed precision engineered exosome therapeutic candidates using PTGFRN as a scaffold to enable high-density surface display of structurally and biologically diverse proteins, including enzymes, antibodies, type I cytokines, and TNF superfamily members. When these proteins were genetically fused to PTGFRN and overexpressed in a producer cell, significantly higher transgene expression on secreted exosomes was achieved compared to previously published scaffolds. PTGFRN-mediated display of CD40L on engineered exosomes resulted in a 15-fold potency increase in B cell activation over recombinant CD40L. Furthermore, expression of CD40L redirected exosome uptake from phagocytic APCs to B cells, demonstrating exosome surface modifications can alter cellular tropism. Codiak exosomes with IL-12 tethered to the surface demonstrated superior tumor retention compared to free cytokine, resulting in robust anti-tumor activity in anti-PD-1 refractory B16F10 tumor models. Additionally, exosomes engineered to overexpress PTGFRN enhanced activity of exosome-mediated delivery of STING agonist, with expression levels positively correlating with IFNβ production and tumor growth inhibition.

Source – BusinessWire