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Parenchyma Biotech Development pipeline
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DEVELOPING NOVEL AHR-TARGETED IMMUNOTHERAPIES FOR AUTOIMMUNE DISEASES AND CANCER
Parenchyma Biotech has a platform whereby we develop AHR-targeted small molecules with the ability to normalize the patient’s immunopathological state or to reprogram the tumor microenvironment toward increased anti-tumor immunity.
AHR
AHR is a nuclear receptor transcription factor controlling the immune system in health and disease. AHR ligands are small molecules originating in the diet, microorganisms, host metabolism, and pollutants. After binding to its ligands, AHR is released from a chaperone complex in the cytoplasm and translocated to the nucleus where it functions as a transcription factor or a transcriptional repressor. Dioxin and tryptophan metabolites represent an exogenous and endogenous AHR ligand, respectively. In general AHR agonists are an immune suppressor that has a significant anti-inflammatory activity for various autoimmune diseases, whereas AHR antagonists potently increase immunity against pathogens and cancer. We are developing novel synthetic AHR agonists and antagonists based on L- kynurenine, an endogenous AHR ligand.
AHR signaling pathway
AHR Agonist As A Promising New Therapeutic for Autoimmune Diseases
AHR ligands are effective in counteracting excessive tissue inflammation of the barrier organs. Because of their poor pharmacokinetics, low efficacy, and toxicity, there are limitations of natural AHR ligands or synthetic AHR agonists in using drugs for diseases. Our progressing product candidate is promising in terms of its safety and therapeutic efficacy for autoimmune diseases.
Recovery of the immune balance
Uncontrolled inflammatory Th17 cells cause autoimmune diseases, including IBD, MS, RA, and psoriasis. Since the discovery of AHR expression in Th17 cells and Treg cells, there has been continued focus on how to shift the balance between Th17 and Treg cells by controlling AHR activities. Our AHR candidate drug has been shown to be effective in decreasing Th17 cells but increasing Treg cells in inflammatory tissues.
Restoration and maintenance of barrier integrity
AHR is an essential regulator of homeostasis for the gut barrier by controlling innate immunity and barrier function. Intestinal epithelial cells actively communicate with luminal microbiota and lamina propria immune cells and AHR plays a central role in recovery of intestinal integrity after injury, such as promotion of crypt stem cell differentiation. Our candidate AHR agonist provides a promise in promoting mucosal healing and microbial homeostasis during intestinal bowel disease (IBD).
Effects of AHR signaling in immune cells and intestinal epithelial cells
AHR Antagonist As A Promising New Approach to Cancer Immunotherapy
Less than a decade ago, the first-generation immunotherapies, called immune checkpoint inhibitors (ICIs), delivered a major breakthrough in cancer therapy. Targeting a pathway that cancer uses to suppress the immune system, ICIs can reactivate the body’s defense with significantly improved outcomes for a subset of cancer patients. Roughly 70% of overall cancer patients do not respond to ICI treatment. There is a strong need for safe, controllable and affordable small molecules that can create the tumor microenvironment (TME) favorable for ICI therapy. Parenchyma Biotech targets the AHR which appears to be a key player in orchestrating immune escape.
Cancer cells constantly fuel the AHR pathway, thus producing tryptophan metabolic AHR ligands. This observation has motivated many companies to develop as anticancer drugs antagonist of indoleamine 2,3-dioxygenase (IDO) that is a rate-limiting enzyme for tryptophan catabolism. The outcomes of clinical trials are disappointing. We believe that AHR antagonist is a better choice for anticancer drugs, since there exist endogenous AHR ligands other than tryptophan metabolites.
Our AHR candidate inhibitor is intended to have a strong anti-tumor immunity within tumors. This aim will be achieved by inducing immune-activating myeloid cells, such as dendritic cells and macrophages, and by repressing production of immunoregulatory molecules by cancer cells. As a result, cancer-killing lymphocytes rather than Treg cells are likely to be dominant within tumors.
Cancer cells constantly fuel the AHR pathway, thus producing tryptophan metabolic AHR ligands. This observation has motivated many companies to develop as anticancer drugs antagonist of indoleamine 2,3-dioxygenase (IDO) that is a rate-limiting enzyme for tryptophan catabolism. The outcomes of clinical trials are disappointing. We believe that AHR antagonist is a better choice for anticancer drugs, since there exist endogenous AHR ligands other than tryptophan metabolites.
Our AHR candidate inhibitor is intended to have a strong anti-tumor immunity within tumors. This aim will be achieved by inducing immune-activating myeloid cells, such as dendritic cells and macrophages, and by repressing production of immunoregulatory molecules by cancer cells. As a result, cancer-killing lymphocytes rather than Treg cells are likely to be dominant within tumors.
Effects of AHR signaling in cancer
