The importance of the stimulator of interferon genes (STING) pathway in orchestrating the bodys innate response to pathogenic, tumor or self-DNA in the cytoplasm has made it a hot target in immunology research and drug discovery, and several biopharma companies have started programs dedicated to that area, spanning infectious and inflammatory diseases as well as cancer. The second part of this feature examines the products undergoing preclinical development as well as the ones that are now in clinical testing.

Preclinical development

In June, Mersana Therapeutics Inc., of Cambridge, Mass., which is developing antibody-drug conjugate (ADC) therapies to treat cancer, closed a public offering of $174.8 million. In its pipeline it has Immunosynthen STING-agonist ADCs and, at the AACR 2020 virtual meeting, it presented preclinical data on multiple candidates that showed complete tumor regressions that were observed after a single dose. Those data also showed that the Immunosynthen STING-agonist ADCs were more active (over 100-fold increased potency) with significantly lower induction of systemic cytokines when compared to intravenously administered unconjugated (free) agonist, demonstrating the potential to confer an improved therapeutic index. In addition, potent ADC-mediated tumor regression led to durable immunological memory in an immune competent model. The company said selection of its first candidate remains on track for this year.

Codiak Biosciences Inc., of Cambridge, Mass., which is working on the development of exosome-based therapeutics targeting solid tumors, filed this month with the SEC to raise up to $100 million in an IPO. The company originally filed for an IPO in April 2019, aiming to raise $86 million, but withdrew it a few months later, citing market conditions.

One of the lead product candidates in the companys pipeline is exoSTING for the treatment of multiple solid tumors. Developed from its engex platform, the company explains that it is designed to selectively activate the STING pathway in tumor-resident antigen-presenting cells and attract and expand immune effector cells in the tumor microenvironment. Data from the companys preclinical studies suggest that, when administered intratumorally, the compound generates potent, targeted and systemic antitumor immunity without inflammatory cytokine-driven adverse events. A phase I/II trial in patients with a select group of solid tumors is being planned.

Boston-based Silicon Therapeutics Inc. reported at the annual AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics last year preclinical studies on its small-molecule, intravenously delivered STING agonist, SITX-799, demonstrating the compound produced robust and durable antitumor immunity and tumor regression.

In vivo studies showed that a single dose of SITX-799 produced complete regression of colon cancer tumors in mice and robust induction of type I interferons. Cured mice were re-challenged with tumors 90 days after initial treatment and remained tumor free, demonstrating durable, antitumor immunity. No antitumor response to treatment was observed in mice lacking a functional immune system, demonstrating the immune-therapeutic mechanism of action. SITX-799 was shown to be well-tolerated and demonstrated a favorable pharmacokinetic profile.

Onxeo SA, of Paris, said preclinical studies show OX-401, a PARP agonist, has strong antitumor activity and immunological properties. OX-401s antitumor activity was demonstrated in an animal model of breast cancer, related to PARP hyperactivation and diversion of its DNA repair function in specific tumor cells, the company said. The activity on PARP induces a strong engagement of the cGAS-STING pathway, as shown by the increase in key biomarkers of the tumor immune response, the company said. The next key preclinical milestone will be a study combining OX401 with immune checkpoint inhibitors.

In the clinic

In a research note, SVB Leerinks Daina Graybosch noted at the ongoing European Society for Medical Oncology (ESMO) virtual meeting, Merck & Co. Inc. reminded us that they are still interested in STING agonism, presenting a trial in progress poster for their phase II proof-of-concept trial in head and neck cancer.

The study is evaluating the efficacy and safety of intratumoral MK-1454, an investigational cyclic dinucleotide STING agonist, plus I.V. Keytruda (pembrolizumab) combination therapy vs. I.V. Keytruda anti-PD-1 antibody monotherapy as first-line treatment for metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).

Cambridge, Mass.-based Synlogic Inc. is using synthetic biology to develop therapeutics. A paper published in Nature Communications highlighted the use for its engineered bacteria to target STING activation in tumors and activate innate immune pathways. The paper highlights preclinical data supporting its first clinical immuno-oncology program, SYNB-1891, which is being evaluated in a phase I trial in patients with advanced solid tumors or lymphoma. Data described in the publication demonstrate that SYNB-1891 treatment cleared tumors and stimulated antitumor immunity in preclinical models of cancer.

The product is an engineered strain of E. coli Nissle, that produces cyclic di-AMP, a stimulator of the STING pathway. Synlogic said it expects to release data from the monotherapy arm of this study late this year. After establishing a maximum tolerated dose as a monotherapy, a planned second arm of the study will involve subjects receiving escalating dose levels of SYNB-1891 in combination with a fixed dose of the checkpoint inhibitor Tecentriq (atezolizumab, Roche Holding AG) to establish a recommended dose for the combination regimen.

Noxopharm Ltd. is developing Veyonda, which has two main drug actions inhibition of sphingosine kinase and inhibition of STING signaling that provides an anti-inflammatory effect, also contributing to an anticancer action, but also potentially blocking sepsis.

It has recently begun a phase I Noxcovid-1 study in COVID-19 patients. The company believes the mechanism of action prevents the progression of the disease via the STING pathway into the cytokine storm leading onto septic shock. The study will involve approximately 40 patients and a range of doses of Veyonda will be administered to patients hospitalized with moderate symptoms who are at high risk of tipping over into a cytokine storm and developing septic shock.

One of the key endpoints is the effect of treatment on blood cytokine levels, and findings of the study are anticipated to be released in early-2021.

Venture capital

Ventus Therapeutics Inc. received $60 million from a series A funding to help leverage insights from its structural biology programs for inflammasome activation and cGAS-Sting signaling. The signal pathways underpinning those two sensory systems contain a significant number of validated drug targets that Ventus will be actively interrogating.

Actym Therapeutics Inc., of Berkeley, Calif., said it completed a $34 million series A financing led by Boehringer Ingelheim Venture Fund and Panacea Venture, with participation from Illumina Ventures, Korea Investment Partners and Jlo Ventures. The company will use the proceeds to advance development of immunotherapies from its microbial-based STACT (S. Typhimurium Attenuated Cancer Therapy) platform into the clinic for the treatment of various cancers, which includes a potentially first-in-class, systemically administered STING pathway agonist.

In May, Toronto-based Portage Biotech Inc. made an additional 900,000 (US$1.05 million) investment in its associate, Stimunity, a Paris-based cancer immunotherapy company focused on STING. The company had reached a significant milestone in its preclinical development plan and the additional financing will enable it to start the manufacturing of its biologic STING activating cGAMP- Virus-Like Particle (STI-001) lead compound.

Read the rest here:
STING: A hot target in immunology research and drug discovery - BioWorld Online