“By naturally modulating a key pathway that AMTX-100 targets, which represents an internal checkpoint used to initiate inflammation, AMTX-100 has the ability to provide broad targeted therapeutic activity without affecting important housekeeping genes essential for cell growth and viability, drastically minimizing side-effects and safety concerns seen with many small molecule and biologic anti-inflammatory drugs.”
Matt Gonda, Ph.D, Amytrx CEO
Inflammatory signals mobilize the innate and adaptive immune systems to respond to and contain pathogens or injuries, playing a critical role in sustaining human health and vitality. But when inflammation is uncontrolled—causing local or systemic or local dysregulation and imbalance of the immune system—it can lead to a range of chronic diseases impacting one's quality of life.
Much of the therapeutic focus on chronic inflammatory diseases has centered on approaches that inhibit inflammatory responses extracellularly with antibodies or penetrate many cell types with small molecules without cell selectivity trying to block a single proinflammatory pathway, all of which can lead to serious side effects and other significant challenges for the body to remove accumulating toxic molecules, which can affect both efficacy and patient safety.
An optimal therapeutic solution should show selectivity for the cells responsible for causing inflammation and broadly modulate, but not inhibit, their inflammatory responses. Using a system of regulation already naturally occurring in cells of the body, AMTX-100 attenuates the stimulation of inflammatory and metabolic pathways by modulating the nuclear transport of transcription factors involved in inflammation or metabolism. Such a solution at a pivotal checkpoint would offer a safer and more effective approach to restoring immune and metabolic balance.
How it Works
When introduced into the body, AMTX-100 is rapidly and broadly distributed. It can enter leukocytes where it competes as a decoy with the NLS of SRTFs involved in inflammation and TFs involved in metabolism for their nuclear transporters—the adaptor molecule Importin α5 (Impα) complexed to importin β1 (Impβ) (Impα/Impβ) or Impβ alone, respectively—without affecting smaller housekeeping TFs. This competition for the NLS docking site on Impα for SRTFs or Impβ for TFs involved in metabolic stress modulates but does not completely inhibit, TF trafficking into the nucleus which leads to attenuation of inflammatory or metabolic gene transcription.
Proinflammatory insults can stimulate cytoplasmic and genomic responses in immune and non-immune cells. Genomic responses depend on translocation of transcription factors (TF) from the cytoplasm to the nucleus to switch on genes and to produce RNA gene transcripts that are translated in the cytoplasm into proinflammatory gene products that are subsequently secreted. Some large proinflammatory TFs are known as stress responsive transcription factors (SRTFs), such as NFAT, NF-kB, c-rel, Rel A,
AP-1, NRF-2, and STAT1. The larger size of SRTFs excludes them from freely entering the nucleus through nuclear pores. Nuclear transport of SRTFs require the assistance of importins, specifically, the adaptor protein Importin α5 (Impα) complexed with importin β1 (Impβ). There is another class of large TFs involved in metabolism that include carbohydrate response element-binding protein (ChREBP) and sterol regulatory element-binding protein (SREBP) that requires only Impβ for nuclear translocation (not shown).
AMTX-100 is a bioactive decoy peptide containing both a cell-penetrating domain and only the nuclear localization sequence (NLS)
of a stress responsive transcription factor (SRTF), NF-kB, that is capable of modulating the inflammatory response by competing with the NLS binding domain on fully functional NF-kB and other monopartite and bipartite NLS containing SRTFs, like c-rel, Rel A, AP-1, NFAT, NRF-2, STAT1, and SREBP (contains a NLS for both Impα and Impβ), for their docking site on the Impα adaptor protein complexed to Impβ. This competition between the NLS’s of AMTX-100 and SRTFs for their cognitive binding site on Impα dilutes the proinflammatory effects
of SRTFs upstream of DNA activation by modulating the amount of functional SRTFs that enter the nucleus and stimulate promoters of inflammatory genes. This reduces the initiation of transcriptional and translational processes resulting in reduced production of proinflammatory cytokines, chemokines, and growth factors. Similarly (not shown), AMTX-100 also contains a second TF binding domain in the cell-penetrating sequences that binds Impβ and competes with transport of the fully functional TFs, SREBP, and ChREBP, involved in activating genes responsible for production and secretion of cholesterol, triglycerides, fatty acids, and carbohydrates involved, in metabolism.
Other Autoimmune Disorders
Diabetic Retinopathy, Sjögren’s
AMTX-100: A Novel Therapeutic Solution with Many Opportunities
Resolution of inflammatory diseases involves an active process of reprogramming cells using mechanisms that limit inflammation to restore immune balance. AMTX-100 is a breakthrough therapeutic approach that can penetrate many responsible for chronic inflammation and disease. It focuses on reprogramming the immune cell’s inflammatory state and in doing so, the peptide provides very efficient anti-inflammatory activity. It is capable of modulating activators of inflammation intracellularly at a commonly used key checkpoint in large stress response transcription factors (SRTFs) nuclear transport, reducing production of many cytokines, chemokines, and growth factors.
AMTX-100 is a first-in-class, cell-penetrating anti-inflammatory peptide with a novel mechanism of action that leverages the tight intracellular control required for nuclear transport of large SRTFs involved in inflammation and transcription factors (TFs) involved in metabolism through their obligatory use of nuclear transporters called importins.
This therapeutic is bioengineered from amino acid sequences of human fibroblast growth factor-4 (FGF-4) and the nuclear localization sequence (NLS) of NF-kB, the master regulator of inflammation. AMTX-100 can readily penetrate leukocytes and actively compete with the natural binding of TFs with an NLS to their docking site on importins used to transport SRTFs from the cytoplasm to the nucleus.
Multiple pre-clinical animal models of human disease in a range of disorders where inflammation or metabolic stressors form the underlying basis of the condition, as well as first-in-human studies in atopic dermatitis, have demonstrated the successful therapeutic benefit and safety of AMTX-100.
Commercialization Advantages of
Excellent systemic and topical safety profile in preclinical studies
Broad application across a range of inflammatory diseases
Versatile and stable product formulations
Strong composition of matter and utility position
Collaborative opportunities for stand-alone or combination treatment
Scalable manufacturing and favorable cost of goods