Siglec-10

– Atopic dermatitis and prurigo nodularis skin lesions show evidence of MRGPRX2 mast cell activation and activated macrophages – – AK006 inhibited mast cell activation and reduced mast cell numbers in an MRGPRX2-induced skin inflammation model – Feb. 26, 2024 -- Allakos Inc. (Nasdaq: ALLK), a clinical-stage biotechnology company developing therapeutics that target immunomodulatory receptors present on immune effector cells involved in allergy, inflammatory and proliferative diseases, today announced a poster presentation at the 2024 American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting. The poster highlights preclinical data detailing AK006’s mechanism of action and ability to reduce MRGPRX2-induced skin inflammation. Inappropriate mast cell activation, via IgE-dependent and IgE-independent pathways, has been implicated in the pathogenesis of multiple inflammatory skin diseases. IgE-dependent mast cell activation has been identified as a pathogenic driver of chronic spontaneous urticaria and food allergy and agents which target this pathway have demonstrated therapeutic activity. More recently, mast cell activation through MRGPRX2, an IgE independent mast cell activation pathway, has been implicated in the pathogenesis of chronic spontaneous urticaria, atopic dermatitis and prurigo nodularis. The poster, titled: “MRGPRX2-Mediated Mast Cell Activation is a Shared Pathogenic Mechanism in Atopic Dermatitis and Prurigo Nodularis Patients that can be Inhibited by Siglec-6” was presented on Friday, February 23rd, key findings include: IgE-independent mast cell activation, via MRGPRX2, has been implicated in atopic dermatitis and prurigo nodularis disease pathogenesis Atopic dermatitis and prurigo nodularis skin lesions contain mast cells displaying signs of MRGPRX2 activation, as well as elevated and activated macrophages AK006 has a dual mechanism of action that inhibits mast cells and reduces mast cells via antibody dependent cellular phagocytosis (ADCP) in the presence of activated macrophages In an MRGPRX2-induced skin inflammation model, AK006 reduced skin inflammation and reduced mast cells numbers via ADCP By broadly inhibiting and reducing mast cells, AK006 has the potential to treat inflammatory skin diseases, such as atopic dermatitis, prurigo nodularis, and chronic spontaneous urticaria The data presented Friday add to previous published preclinical data demonstrating that AK006 inhibits both IgE-dependent and IgE-independent mast cell activation and can reduce mast cell numbers at sites of inflammation where activated macrophages are found. AK006 is a humanized IgG1 monoclonal antibody which activates the inhibitory receptor Siglec-6. Siglec-6 is a member of the family of cell surface receptors called Sialic acid-binding immunoglobulin-like lectins (Siglecs). Siglec-6 is expressed primarily on the surface of mature mast cells. Siglec-6 contains intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) which, when activated, recruit phosphatases that work to oppose activating signals driven by kinase signaling cascades. Because of this opposition to multiple activation pathways, AK006 has the potential to inhibit multiple modes of mast cell activation and has demonstrated preclinical inhibition of mast cell activation by IgE and through MRGPRX2 and KIT receptors. ITIM bearing receptors have important roles in regulating the immune system and therapeutics targeting ITIM bearing receptors, such as PD-1 and Siglec-10, have demonstrated therapeutic activity in oncology and immunology. AK006 appears to drive deep mast cell inhibition and, in addition to its inhibitory activity, can reduce mast cell numbers via antibody-dependent cellular phagocytosis in the presence of activated macrophages. AK006 is currently being tested in a Phase 1 study in healthy volunteers and will begin dosing in early 2Q 2024 in patients with chronic spontaneous urticaria. Results from the Phase 1 study are expected throughout 2024. Allakos is a clinical stage biotechnology company developing therapeutics that target immunomodulatory receptors present on immune effector cells involved in allergy, inflammatory and proliferative diseases. Activating these immunomodulatory receptors allows for the direct targeting of cells involved in disease pathogenesis and, in the setting of allergy and inflammation, has the potential to result in broad inhibition of inflammatory cells. The Company’s most advanced antibody in ongoing clinical development is AK006. AK006 targets Siglec-6, an inhibitory receptor expressed on mast cells. Mast cells are widely distributed in the body and play a central role in the inflammatory response. Inappropriately activated mast cells have been identified as key drivers in a number of severe diseases affecting the gastrointestinal tract, eyes, skin, lungs and other organs. In preclinical studies, AK006 appears to provide deep mast cell inhibition and, in addition to its inhibitory activity, reduce mast cell numbers. For more information, please visit the Company’s website at www.allakos.com. The content above comes from the network. if any infringement, please contact us to modify.

– Data provide insights on the signaling pathways involved with AK006 mast cell inhibition –– AK006 has a distinct mechanism of action that leads to broad inhibitory effects on mast cells – SAN CARLOS, Calif., Feb. 12, 2024 (GLOBE NEWSWIRE) -- Allakos Inc. (Nasdaq: ALLK), a clinical-stage biotechnology company developing therapeutics that target immunomodulatory receptors present on immune effector cells involved in allergy, inflammatory and proliferative diseases, today announced the publication of new scientific results in Allergy. The preclinical research found that AK006 (agonist Siglec-6 antibody) impacts mast cell function by interacting with multiple activating receptors and key signaling molecules. The publication titled “Regulation of Mast Cells by Overlapping but Distinct Protein Interactions of Siglec-6 and Siglec-8” details efforts to identify proteins associated with Siglec-6 and Siglec-8 in mast cells and functionally characterize these protein interaction networks using ex vivo and in vivo models of mast cell activation. The data published today add to previously published preclinical data demonstrating that AK006 inhibits multiple modes of mast activation. As detailed in the Allergy publication, proteomic profiling of mast cells revealed Siglec-6 and Siglec-8 interact with a large cluster of proteins involved in IgE and non-IgE-mediated mast cell activation, including the high affinity IgE receptor (FcεRI), IL-4 and IL-33 receptors, and intracellular kinases LYN and JAK1. Importantly, Siglec-6 was found to interact with multiple critical regulatory proteins that do not interact with Siglec-8, including stem cell factor (SCF) receptor KIT/CD117, different subunits of the FcεRI receptor and proteins modulating metabolic processes. These findings suggest Siglec-6 has a broader role in regulating mast cell function and may contribute to the increased inhibitory effects observed with AK006 in vitro and in vivo. The publication is both available on the Allergy website as well as Allakos Scientific Presentations page. About AK006 AK006 is a humanized IgG1 monoclonal antibody which activates the inhibitory receptor Siglec-6. Siglec-6 is a member of the family of cell surface receptors called Sialic acid-binding immunoglobulin-type lectins (Siglecs). Siglec-6 is expressed primarily on the surface of mature mast cells. Siglec-6 receptors contain intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) which, when activated, recruit phosphatases that work to oppose activating signals driven by kinase signaling cascades. Because of this opposition to multiple activation pathways, AK006 has the potential to inhibit multiple modes of mast cell activation and has demonstrated preclinical inhibition of mast cell activation by IgE and through MRGPRX2 and KIT receptors. ITIM bearing receptors have important roles in regulating the immune system and therapeutics targeting ITIM bearing receptors, such as PD-1 and Siglec-10, have demonstrated therapeutic activity in immunology and oncology. AK006 appears to drive deep mast cell inhibition and, in addition to its inhibitory activity, can reduce mast cell numbers via antibody-dependent cellular phagocytosis (ADCP) in the presence of activated macrophages. AK006 is currently being tested in a Phase 1 study in healthy volunteers and will begin dosing in early 2Q 2024 in patients with chronic spontaneous urticaria. Results from the Phase 1 study are expected throughout 2024. About Allakos Allakos is a clinical stage biotechnology company developing therapeutics that target immunomodulatory receptors present on immune effector cells involved in allergy, inflammatory and proliferative diseases. Activating these immunomodulatory receptors allows for the direct targeting of cells involved in disease pathogenesis and, in the setting of allergy and inflammation, has the potential to result in broad inhibition of inflammatory cells. The Company’s most advanced antibody in ongoing clinical development is AK006. AK006 targets Siglec-6, an inhibitory receptor expressed on mast cells. Mast cells are widely distributed in the body and play a central role in the inflammatory response. Inappropriately activated mast cells have been identified as key drivers in a number of severe diseases affecting the gastrointestinal tract, eyes, skin, lungs and other organs. In preclinical studies, AK006 appears to provide deep mast cell inhibition and, in addition to its inhibitory activity, reduce mast cell numbers. For more information, please visit the Company’s website at www.allakos.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 as contained in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Such forward-looking statements include, but are not limited to, Allakos’ progress, business plans, areas of focus and preclinical research; the potential of AK006; and Allakos’ anticipated milestones. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from current expectations and beliefs, including but not limited to: Allakos’ stages of clinical drug development; Allakos’ ability to timely initiate and complete clinical trials for AK006; Allakos’ ability to obtain required regulatory approvals for its clinical trials; uncertainties related to the enrollment of patients in its clinical trials; Allakos’ ability to demonstrate sufficient safety and efficacy of its product candidates in its clinical trials; uncertainties related to the success of clinical trials, regardless of the outcomes of preclinical testing or early-stage trials; Allakos’ ability to advance additional product candidates beyond AK006; uncertainties related to Allakos’ ability to realize the contemplated benefits of its restructuring and related reduction in force; Allakos’ ability to accurately forecast financial results; Allakos’ ability to obtain additional capital to finance its operations, research and drug development; general economic and market conditions, both domestic and international; domestic and international regulatory obligations; and other risks. Information regarding the foregoing and additional risks may be found in the section entitled “Risk Factors” in documents that Allakos files from time to time to with the SEC. These documents contain and identify important factors that could cause the actual results for Allakos to differ materially from those contained in Allakos’ forward-looking statements. Any forward-looking statements contained in this press release speak only as of the date hereof, and Allakos specifically disclaims any obligation to update any forward-looking statement, except as required by law. These forward-looking statements should not be relied upon as representing Allakos’ views as of any date subsequent to the date of this press release. Source: Allakos Inc. Investor Contact:Adam Tomasi, PresidentAlex Schwartz, VP Strategic Finance and Investor Relationsir@allakos.com Media Contact:Denise Powelldenise@redhousecomms.com

HANGZHOU, China, Dec. 20, 2023 /PRNewswire/ -- Recently, a CAR-macrophage therapy product (CAR-M) SY001 from CellOrigin Biotechnology (Hangzhou) Co., Ltd. was dosed to the first patient in a hospital in China. "A single center, single-arm, dose-escalation, exploratory clinical trial to examine the safety, tolerability, pharmacokinetics and preliminary efficacy of SY001 from CellOrigin Biotechnology in patients with advanced solid tumors" is the first investigator-initiated clinical study of CAR-M cell therapy product in China. The successful completion of the first patient dosing of SY001 demonstrates the advanced technology of the company's R&D platform and the maturity of the CMC platform. Currently, the clinical study is actively recruiting patients. SY001 was well tolerated and no dose-limiting toxicity (DLT) was observed (n=2). Only 2 grade 3 adverse events occurred; Common grade 1 - 2 adverse events included fever, elevated C-reactive protein, etc. No cytokine release syndrome or neurotoxicity related to cell infusion occurred in any patients. The clinical data of CAR-M products up to now suggest the excellent safety and certain clinical benefits of macrophage immunotherapy. CellOrigin expects that this innovative product will prove its safety and effectiveness in clinical trials, bringing new hope for the treatment of solid tumors, thereby improving patients' quality of life and prolonging their life span. Besides, in November 2023, CellOrigin collaborated with Zhejiang University to publish a paper entitled "A second generation M1-polarized CAR macrophage with antitumor efficacy" in Nature immunology, designing an exclusive CAR with antigen-dependent polarization and activation of macrophage function (TIR-CAR or M-CAR) by introducing the TIR signal transduction domain. Based on M-CAR, a functionally enhanced second generation CAR-iMAC has been developed to enhance the effectiveness of the therapy for solid tumors. The mechanism of antigen-dependent activation and polarization of the second generation CAR-iMAC and the mechanisms of solid tumor cell killing were also revealed. In November 2020, the team published a paper in J Hematol Oncol entitled "Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions." It opens the door for human iPSC-derived CAR-macrophage (CAR-iMAC) and its applications in targeted anti-tumor research. The first generation CAR-iMAC was designed, and was capable of carrying out the antigen-dependent killing of tumor cells. On September 11, 2023, the team collaborated with Dr. Wang Ben's Research Group of Zhejiang University to publish a paper entitled "Targeted glycan degradation potentials cellular immunotherapy for solid tumors" in Proceedings of the National Academy of Sciences (PNAS). The collaboration found that simultaneous deletion of sialidase-binding immune checkpoints Siglec-5 and Siglec-10 (DKO-CAR-iMac) on macrophages significantly enhanced CAR-iMAC's anti-solid tumor function. Almost the same time, the team published another paper entitled "Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophases in solid tumors" in Nature communications. A CRISPR Screen method was used to find the key metabolic genes related to CAR-iMAC polarization in tumor microenvironment. It was discovered that knockout of ACOD1 (or IRG1) could improve macrophage proinflammatory polarization, phagocytic capacity and tumor-killing activity. Furthermore, the study also found that the anti-tumor effect of ACOD1-/- MSLN-CAR-iMAC can be further enhanced by combining immune checkpoint inhibitors. These findings offer fresh concepts for remodeling macrophages based on metabolic reprogramming or editing the immune checkpoints. Based on these research results, CellOrigin is conducting a series of pre-clinical and clinical studies of CAR-macrophage therapies for solid tumors in an effort to provide patients with safe and effective treatment choices as soon as possible. About CellOrigin: CellOrigin is committed to the development and clinical translation of their proprietary CAR-expressing iPSC-derived immune cells such as CAR-iMAC. They have obtained engineered immune cells derived from iPSC using cutting-edge technologies including gene editing and synthetic biology. CellOrigin takes advantage of the unique characteristics of macrophages that can infiltrate the solid tumor microenvironment (TME), and is developing CAR-M products mainly for relapsed/refractory solid tumors. They have completed the establishment of a clinical-grade iPSC cell bank, independently developed the CMC process of CAR-iMAC cells that can be produced in large scale to meet the amount for off-the-shelf products, and established a complete GMP quality system and corresponding quality control methods. They are collaborating with domestic and international hospitals for clinical trials, and also seeking for opportunities of licensing of the technology platform and certain pipelines. For more information,please contact Yaoyao Li, [email protected]. SOURCE CellOrigin