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Replies to post #485890 on NorthWest Biotherapeutics Inc (NWBO)
06/12/22 5:40 PM
TLR Agonists
The activators of the present disclosure include those the stimulate Pattern Recognition Receptor (PRR) -dependent cellular responses. Pattern Recognition Receptors include Toll-like Receptors (TLRs), RIG-1 like Receptors (RLRs), NOD -like receptors (NLR) and C-type Lectin Receptors (CLRS). PRRs act to either directly or indirectly detect molecules that are common to broad classes of microbes. These molecules are classically referred to as pathogen associated molecular patterns and include factors such as bacterial lipopolysaccharide (LPS), bacterial flagellin, or viral double stranded RNA. TLRs, as above, are a class of pattern recognition receptors (PRRs), which detect microbial molecules classically referred to as pathogen associated molecular patterns (PAMPs). The TLR immune receptors are expressed on the membranes of leukocytes, including dendritic cells, and the binding of TLR agonists triggers molecular events that can lead to an immune response and antigen-specific acquired immunity. Many TLR agonists are also dendritic cell maturation agents as discussed below. Bacterial lipopolysaccharide (LPS) is a strong agonist of TLR4 with the ability to enhance immune responses to soluble antigens. LPS stimulates immune system cells by the TLR4 pathway, which recognizes common PAMPs. Additional TLR agonists include synthetic molecules, such as for example, Poly I:C which binds TLR3, Pam2CSK4 (Pam2) which binds and activates the TLR 2 and TLR 6 pathways, Pam3CSK4 (Pam3) which binds and activates the TLR 2 and TLR1 pathways, and R848 and R837 which are imidazoquinolines which bind and activate the TLR 7 and TLR 8 pathways. Unmethylated CpG motif sequences (oligodeoxynucleotides (ODNs) common to certain bacteria bind to and activate TLR9.
In specific embodiments of the methods described herein the TLR agonist can be a bacterial or microbial product and be a bacterial LPS, such as, for example, an E. coli LPS or an LPS derived or isolated from any other bacterial that have an LPS (e.g., monophosphoryl lipid A (MPLA)), bacterial cell membranes or cell wall skeleton, and the like. The bacteria or bacterial product can also be, for example, another TLR4 agonist BCG or products of BCG including, for example, cell wall constituents, BCG-derived lipoarabidomannans, and other BCG products. BCG is optionally inactivated, such as heat- inactivated BCG, formalin-treated BCG, or by a combination of heat and other inactivation methods. In other examples the TLR agonist can be Poly I:C, Pam2CSK4, Pam3CSK4, R848, R837, or an ODN where the optimal CpG motif for human appears to be GTCGTT.
“Other maturation factors include prostaglandin E2 (PGE2), poly-dldC, vasointestinal peptide (VIP), bacterial lipopolysaccharide (LPS), Bacillus Calmette-Guerin (BCG), as well as other mycobacteria or components of mycobacteria, such as specific cell wall constituents.
Enhancement of IL-12 production by dendritic cells has been reported by combining interferon gamma (IENg) with certain dendritic cell maturation factors, such as bacterial lipopolysaccharide (LPS), BCG, and CD40L. LPS, BCG and CD40L have a known capacity to induce small amounts of IL-12 during maturation, however. In addition, BCG has been shown to induce substantial amounts of IL-10, thus originally thought to induce a Th2 immune response when used alone. It has now been shown that the addition oflFNy enhances the production of IL-12 when combined with LPS, BCG or CD40L when added to immature dendritic cells cultured in vitro. Interferon gamma signaling uses the Jak2-Statl pathway, which includes tyrosine phosphorylation of the tyrosine residue at position 701 of Statl prior to its migration to the nucleus and the ensuing enhancement of transcription of interferon gamma-responsive genes. Still little is known, however, about signal transduction pathways in human monocyte-derived dendritic cells. The mechanism for IFNy action in these cells has not been fully established.
Recently, it has been shown that hyperactive DCs secrete inflammatory cytokines from the cytosol (e.g., IL-Ib) and biosynthetic pathways (e.g., TNPa) while maintaining viability. These attributes have been achieved by a variety of microbial or host-derived products, including a mixture of oxidized phospholipids, such as oxidized 1 -palmitoyl-2-arachidonyl-.v«-glycero-3-phosphorylcholine (oxPAPC), its substituents and derivatives.
The Interleukin- 1 (IL-1) family of cytokines, including IL-1 and IL-18, play a role in T cell biology generally, and particularly in memory T cell generation and effector function of CD8+ T cells. In addition, IL-1 activates intrinsic IL-1 receptor (IL-1R) signaling in pre-committed T helper (TH) cell lineages, and acts as a signal for increased T effector cytokine production. IL-1 usage has been suggested as an adjuvant in weak or inefficient vaccines, to increase vaccination protection activity. Accordingly, inflammation- activators such as oxidized phospholipids have been examined as inducers of hyperactive dendritic cells in vivo capable of enhancing hyperactivation of dendritic cells and inducing an improved antigen specific immune response when the oxidized lipids are administered to a patient with an immunogen.”
EP4041298A1
European Patent Office
Find Prior Art Similar
Other languages GermanFrench Inventor Marnix Leo BOSCHLinda F. POWERS Current Assignee Northwest Biotherapeutics LLC
Worldwide applications
2020 AU BR KR EP WO CA 2022 IL
Application EP20875158.6A events
Priority claimed from US201962912005P
2020-10-07
Application filed by Northwest Biotherapeutics LLC
2022-08-17 Publication of EP4041298A1
01/11/23 11:29 AM
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