RGI-3100 / Regimmune - LARVOL DELTA

Amide-Linked C4″-Saccharide Modification of KRN7000 Provides Potent Stimulation of Human Invariant NKT Cells and Anti-Tumor Immunity in a Humanized Mouse Model. (PubMed, ACS Chem Biol) - "In silico analysis suggested that the tether length and degree of flexibility of the amide substituent affected the recognition by iNKT cell antigen receptors of the C4″-amide substituted glycolipids in complex with their antigen presenting molecule CD1d. Our findings establish the use of stable C4″-amide linked additions to the sugar moiety for further exploration of the immunological effects of structural modifications of iNKT cell activating glycolipids and highlight the critical need for more accurate animal models to assess these compounds for immunotherapeutic potential in humans."

Journal • Preclinical • Immunology • Oncology

[VIRTUAL] Pharmacokinetics and Safety of KRN7000 Following Intravenous Infusion of RGI-2001 in Allogeneic Transplant Patients (ASH 2020) - "Plasma levels of RGI-7000 were similar after the first dose and multiple doses. Its plasma half-life was approximately 36 hours."

Clinical • PK/PD data • Dermatology • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Mucositis • Oncology • Pruritus • Transplantation • IL4

Supramolecular organization of α-galactosylceramide in pure dispersions and in cationic DODAB bilayers. (PubMed, Chem Phys Lipids) - "α-galactosylceramide (α-GalCer; KRN7000) strongly stimulates NKT cells...Apparently, the effect of the amide bond configuration is a key structural feature for the interaction between ceramide-based glycolipids and DODAB molecules, since we have previously reported a similar decrease of gel phase packing and increase in fluid phase rigidity for DODAB bilayers containing C24:1β-glucosylceramide. Since the structure of delivery systems is critical to the biological activity of α-GalCer, this work certainly contributes to the planning and development of novel immunotherapeutic tools."

Journal

Optical Control of Cytokine Production Using Photoswitchable Galactosylceramides. (PubMed, Chemistry) - "The azobenzene derivative α-GalACer-4 proved to be more potent than KRN-7000 itself when activated with 380 nm light. Photolipids of this type could improve our mechanistic understanding of cytokine production and could open new directions in photoimmunotherapy."

Journal • Immune Modulation • Inflammation • Oncology

A Designed α-GalCer Analog Promotes Considerable Th1 Cytokine Response by Activating the CD1d-iNKT Axis and CD11b-Positive Monocytes/Macrophages. (PubMed, Adv Sci (Weinh)) - "α-galactosylceramide (α-GalCer, KRN7000), a well-studied Th1-polarizer, simultaneously induces helper T cell 2 (Th2)-type responses, which is a major drawback for its clinical applications...Together, the data demonstrate a new mechanism through which α-GalCer-diol induces stronger Th1-type responses by stimulating CD11b leukocyte expansion and DC-conducted CD1d-restricted and TCR-mediated iNKT activation. Hence, this study may facilitate the development of novel Th1 priming agonists."

Journal • Melanoma • Oncology • Solid Tumor • IL12A • ITGAM

A Novel Liposome Formulation Carrying Both an Insulin Peptide and a Ligand for Invariant Natural Killer T Cells Induces Accumulation of Regulatory T Cells to Islets in Nonobese Diabetic Mice. (PubMed, J Diabetes Res) - "Cotransfer of diabetogenic T cells and splenocytes of NOD mice treated with RGI-3100-iB, but not liposomal α-GalCer encapsulating an unrelated peptide, to NOD-SCID mice resulted in the prevention of diabetes and elevation of Foxp3 mRNA expression in the islets. These data indicate that the migration of insulin B-peptide-specific Tregs to islet of NOD mice that are involved in the suppression of pathogenic T cells related to diabetes onset and progression could be enhanced by the administration of liposomes containing α-GalCer and insulin B peptide."

Journal • Preclinical

Synthesis of CH-linked α-galactosylceramide and its glucose analogues through glycosyl radical-mediated direct C-glycosylation. (PubMed, Chem Commun (Camb)) - "We describe a new synthetic approach for C-linked glycolipid analogues, in which the cleavable O-glycosidic linkage is replaced by a carbon unit. Direct C-glycosylation of a conformationally constrained and stable C1-sp3 hybridized xanthate carbohydrate with carefully designed sphingosine units afforded the CH2-linked analogue of antitumor-active KRN7000 and its glucose congener."

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Design and Discovery of Covalent α-GalCer Derivatives as Potent CD1d Ligands. (PubMed, ACS Chem Biol) - "An α-galactosyl ceramide (α-GalCer, KRN7000) is the representative CD1d ligand that can bind to the CD1d protein...Furthermore, the LC-MS/MS analysis indicated that the chloroacetylamide-containing ligand was covalently bound to Cys12 of CD1d, which suggests that the enhanced activities result from the formation of a stable CD1d-ligand complex. To our knowledge, this is the first ligand that allows covalent bond formation to CD1d under physiological conditions."

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Synthesis of polyfluoroalkyl sp-iminosugar glycolipids and evaluation of their immunomodulatory properties towards anti-tumor, anti-leishmanial and anti-inflammatory therapies. (PubMed, Eur J Med Chem) - "Immunomodulatory glycolipids, among which α-galactosylceramide (KRN7000) is an iconic example, have shown strong therapeutic potential in a variety of conditions ranging from cancer and infection to autoimmune or neurodegenerative diseases...Biochemical and computational data further support a mechanism of action implying binding to the allosteric lipid binding site of p38 MAPK and subsequent activation of the noncanonical autophosphorylation route. The ensemble of results provide a proof of concept of the potential of sp-IGLs as immunoregulators."

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Tweaking α-galactoceramides: Probing the dynamical mechanisms of improved recognition for invariant natural killer T-cell receptor in cancer immunotherapeutics. (PubMed, Curr Pharm Biotechnol) - "Findings extracted from this study further reveal important atomistic perspectives that could aid in the design of novel α-GalCer derivatives for cancer immunotherapeutics."

Journal

4"-O-Alkylated α-Galactosylceramide Analogues as iNKT-Cell Antigens: Synthetic, Biological, and Structural Studies. (PubMed, ChemMedChem) - "Yet, the benzyl-modified glycolipids are able to produce a distinct pro-inflammatory immune response. The crystal structures suggest an extra hydrophobic interaction between the benzyl moiety and the α2-helix of CD1d."

Journal

RGI-2001 for the Prevention of Acute Graft-vs-Host Disease in Subjects Following Allogeneic Hematopoietic Stem Cell Transplantation (clinicaltrials.gov) - P2; N=50; Recruiting; Sponsor: Regimmune Corporation; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

Intravenous Administration of RGI-2001 in Patient Undergoing Allogenic Hematopoietic Stem Cell Transplantation (AHSCT) (clinicaltrials.gov) - P1/2; N=68; Completed; Sponsor: Regimmune Corporation; Active, not recruiting ➔ Completed

Trial completion

Culture-Expanded Human Invariant Natural Killer T Cells Suppress T-Cell Alloreactivity and Eradicate Leukemia. (PubMed, Front Immunol) - "Three weeks of cell culture and autologous restimulation with either KRN7000, PBS44, or PBS57 resulted in a robust proliferation of iNKT cells from human PBMCs...Importantly, culture-expanded donor iNKT cells promoted robust antileukemia activity against HLA-matched allogeneic patient leukemia cells. Our data indicate that the adoptive transfer of culture-expanded iNKT cells could be a powerful cytotherapeutic approach to induce immune tolerance and prevent leukemia relapse after allogeneic HCT in humans."

Journal • Preclinical

Thermodynamic and structural behaviour of α-Galactosylceramide and C6-functionalized α-GalCer in 2D layers at the air-liquid interface. (PubMed, Chembiochem) - "However, the first-order phase transition found for the C6-functionalized α-GalCer is connected with an extraordinary surface inhibited nucleation. Our study demonstrates that KRN7000 can be functionalized at C6 without significantly changing the structural properties."

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