BLACKSBURG, Va.--(BUSINESS WIRE)--The NIMML Institute, (“NIMML”), a 501 (c)(3) nonprofit institute dedicated to the discovery of novel precision medicines for infectious and autoimmune diseases, today announced that it will present four abstracts regarding novel mechanistic insights related to the pharmacological activation of LANCL receptors at Immunology2024, the 107th Annual Meeting of the American Association of Immunologists (“AAI”). The AAI meeting will take place at McCormick Place in Chicago, Illinois from May 3 to May 7, 2024.
“We are pleased to present our most recent findings related to the immunometabolic mechanisms of activation of LANCL receptors in inflammation & immunology at this year’s AAI Annual Meeting,” said Dr. Josep Bassaganya-Riera, President and Founding Director of NIMML. “Our findings further demonstrate the value of NIMML’s advanced computational modeling and A.I.-powered TITAN-X Precision Medicine Platform, which continues to efficiently accelerate the discovery and development of biomarker-driven immunoregulatory therapeutic candidates. Leveraging TITAN-X, our findings show that activating LANCL receptors provides therapeutic efficacy in ulcerative colitis (UC), Crohn’s disease (CD), psoriasis, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, asthma, MASH, and Alzheimer’s disease.”
As part of a precision medicine research collaboration with NIMML, NImmune Biopharma, a private late-clinical-stage precision immunology biopharmaceutical company focused on the discovery and development of first-in-class and best-in-class biomarker-driven immunoregulatory therapeutics, utilizes TITAN-X to advance the development of its LANCL portfolio of therapeutics. NImmune’s portfolio includes first and best-in-class omilancor and NIM-1324, two oral, once-daily agonistic therapeutics that bind and activate the LANCL2 pathway. Omilancor is designed for targeted delivery in the gastrointestinal tract for IBD indications and is the first LANCL2 drug in Phase 3 clinical development, and NIM-1324 is designed to be highly systemically distributed for indications such as lupus and rheumatoid arthritis and is currently in Phase 2 clinical development. Omilancor’s and NIM-1324’s strong clinical validation of the novel LANCL mechanism of action demonstrates the importance of the NIMML’s TITAN-X platform in facilitating the discovery and development of a growing pipeline of LANCL drugs for other autoimmune indications.
Presentation Details
Title: Pharmacological activation of LANCL2 provides immunometabolic support for the restoration of cognitive function markers in a mouse model of Alzheimer’s disease.
Poster: B575, Monday May 6, 11:30 AM -12:45 PM CT
- LANCL2 expression is decreased in the brains of 3xTg mice, a well-established mouse model of Alzheimer’s disease, as well as human patients with Alzheimer’s disease.
- LANCL2 deficiency in macrophages resulted in increased inflammatory responses such as IL-6 and IL-1β and altered phagocytosis.
- Activation of LANCL2 using a first-in-class, oral, once-daily small molecule therapeutic reduced inflammatory immune cells (including neutrophils and effector T cells) and decreased the expression of key markers associated with impaired cognitive function in the brain of 3xTg mice.
- Oral treatment prevented the polarization of microglia into a reactive phenotype associated with lesser phagocytic capacity and greater production of inflammatory cytokines, while also supporting the metabolic demands of amyloid beta phagocytosis.
Title: LANCL receptors reduce eosinophilia, type 2 immune responses and lung inflammatory pathology in mouse models of asthma.
Poster: B754, Monday May 6, 2:15 PM - 3:30 PM CT
- Airway hyperresponsiveness and asthma have recently been associated with altered glucose metabolism with inhibition of anaerobic glycolysis reducing inflammatory cytokines and lung eosinophilia.
- Activation of LANCL receptors with a small-molecule agonist decreased the differentiation of inflammatory and allergic CD4+ T cells and the production of inflammatory cytokines by macrophages.
- Oral LANCL agonist treatment in the ovalbumin (OVA) model of asthma reduced lung neutrophilia and eosinophilia, the anti-OVA IgE titer and production of type 2 cytokines IL-5 and IL-13.
- In the house dust mite (HDM) model of asthma, oral LANCL agonist also reduced pulmonary eosinophilia and type 2 immune responses.
- In both OVA and HDM models, LANCL activation resulted in lung gene expression profiles consistent with improved pulmonary function and mitochondrial metabolism.
Title: Pharmacological activation of LANCL receptors has three-fold benefit in metabolic dysfunction-associated steatohepatitis (MASH)
Poster: B908, Monday May 6, 2:15 PM - 3:30 PM CT
- Deficiency of LANCL2 or LANCL3 in mice resulted in increased production of inflammatory cytokines IL-17 and TNF in CD4+ T cells.
- Production of COL1A1 in hepatic stellate cells increased three-fold after TGF-β stimulation in the knockouts relative to wild-type controls.
- LANCL knockout mice fed high fat diet for 12 weeks displayed increased liver weight and decreased glucose tolerance compared to wild-type controls.
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Oral treatment with a small molecule LANCL agonist in both carbon tetrachloride and choline deficient L-amino acid defined (CDAA) models of MASH favorably modulated the three hallmarks of MASH:
- Reduction of fibrosis as measured by a decrease in total collagen and perivascular and bridging deposition.
- Normalization of metabolic parameters as measured by decreased liver weight and plasma triglycerides.
- Decreased inflammation characterized by decreased numbers of Th17 cells and TNF-producing macrophages.
Title: Pharmacological activation of LANCL2 ameliorates disease severity and decreases inflammation in a preclinical model of rheumatoid arthritis
Poster: Board Number B910, Monday May 6, 2:15 PM - 3:30 PM
- NIM-1324 an oral, once-daily, first-in-class, systemically distributed LANCL2 small molecule therapeutic ameliorated disease activity, joint pathology, and redness and swelling in a mouse model of collagen-induced arthritis.
- Immunologically, treatment with NIM-1324 reduced systemic inflammation, decrease effector CD4+ T cells and TNF-producing myeloid cells while the Treg compartment was enhanced.
- LANCL2 deficiency in mice resulted in increased disease severity, inflammatory pathology, and frequency of inflammatory/effector cell subsets.
- Translational studies in human peripheral blood mononuclear cells (PBMC) suggest that NIM-1324 treatment reduced the secretion of inflammatory mediators.
The posters will be available at the AAI 2024 ePoster Hall during and after the meeting. Additionally, the posters and peer-reviewed accepted abstracts will be published verbatim in the “Publications” section of NIMML’s website at www.nimml.org.
About NIM-1324
NIM-1324 is an oral, systemically distributed, small-molecule therapeutic candidate which activates LANCL2, a surface membrane-associated receptor that is responsible for modulating key cellular and molecular changes tied to autoimmune diseases. By activating the LANCL2 pathway, NIM-1324 increases the anti-inflammatory capacity and stability of regulatory CD4+ T cells while also supporting the metabolic demands of autophagy in phagocytes. To date, treatment with NIM-1324 has reduced the production of interferon alpha in human peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients and provided protection from clinical disease and tissue pathology in mouse models of lupus, rheumatoid arthritis, and multiple sclerosis. Phase 2-ready NIM-1324 completed Phase 1 clinical testing where it met all endpoints and demonstrated a dose proportional change in plasma exposure within the therapeutic range with no accumulation. NIM-1324 target U.S. market size is expected to be valued at $226.0 billion 2021-2030, of which a peak annual market size of $23.1 billion is expected to occur in 2030. NImmune expects unadjusted revenue estimates from NIM-1324 therapeutics to be valued at $2.3 billion from the 2028-2030 projections.
About Systemic Lupus Erythematosus (SLE)
SLE is a chronic autoimmune disorder that causes systemic inflammation and organ damage. SLE can affect the skin, joints, blood vessels, kidneys, lungs, brain, and heart, resulting in fatigue, skin rashes or lesions, fevers, arthritis, lung, heart and kidney damage, seizures, and psychosis. SLE symptomatology often results in low quality of life, and 17% of SLE patients will need a kidney transplant. SLE affects over 1.5 million patients in the United States and over 5 million patients worldwide. With more than half of patients experiencing at least one flare per year or presenting persistently active disease, there is an unmet medical need in SLE for the development of safer and more effective therapeutics.
About Rheumatoid Arthritis (RA)
Rheumatoid arthritis (RA) is an autoimmune disease characterized by over-activation of the immune system and increased immune cell infiltration that results in chronic pain and loss of mobility due to excessive inflammation that swell joints and erode bone and cartilage. Current therapies in RA have limitations tied to safety and efficacy and are often accompanied by a high risk of severe side effects and co-morbidities. Furthermore, RA requires chronic treatment to maintain clinical remission. RA affects 1.3 million patients in the United States, with the number of new cases expected to increase as the elderly population grows. According to Global Data, in 2021, sales of prescription drugs to treat RA are estimated to total $20.9 billion. The US currently comprises approximately 74% of the total global prescription sales.
About the TITAN-X Platform
The TITAN-X Precision Medicine Platform combines A.I. methodologies, bioinformatics, and advanced computational modeling to accelerate the development of precision medicines to address the unmet clinical needs of patients with autoimmune diseases. Building upon NIMML’s expertise in engineering large-scale computational models to study immunity as a massively and dynamically interacting system, the TITAN-X Platform integrates each step from new target discovery to enabling biomarker-driven precision clinical drug development. Following bioinformatic analysis of differentially expressed genes from patient biopsy specimens, the TITAN-X Platform can identify transcriptional predictive signatures by using its advanced A.I. algorithms. By analyzing gene expression patterns and integrating clinical data, the TITAN-X Platform can identify responder patterns, facilitating precision medicine approaches for drug development. This ensures that patients receive therapies that are most likely to benefit them according to their unique genetic signatures and clinical profiles, and that are tailored to maximize efficacy, safety, tolerability and minimize adverse side effects. The TITAN-X platform has shaped the development of immunoregulatory therapeutics like omilancor, NX-13 (acquired by Abbvie in March 2024) and NIM-1324.
About NIMML
The NIMML Institute is a 501 (c) (3) non-profit foundation focused on applying transdisciplinary, team-science approaches to precision medicine. The NIMML Institute applies its TITAN-X advanced A.I.-powered platform to large-scale transdisciplinary projects aimed at solving important public health problems through precision medicine. NIMML combines the expertise of immunologists, computational biologists, toxicologists, computational modelers, translational and clinical researchers, and molecular biologists to translate novel scientific discoveries into medicines for human diseases. The Institute is headquartered in Blacksburg, VA. For more information, please visit www.nimml.org or contact pio@nimml.org.