Lirentelimab

Last updated
Lirentelimab
Monoclonal antibody
Type Whole antibody
Source Human
Target SIGLEC8
Clinical data
Trade names AK002
Routes of
administration
Intravenous
Identifiers
CAS Number
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C6408H9884N1700O2006S46
Molar mass 144308.221 g·mol−1

Lirentelimab (sold under the brand name AK002) is a humanized nonfucosylated monoclonal antibody that targets sialic acid-binding Ig-like lectin 8 (SIGLEC8). In a randomized clinical trial, lirentelimab was found to improve eosinophil counts and symptoms in individuals with eosinophilic gastritis and duodenitis. [2] Adverse reactions include infusion reactions, which are mild to moderate and typically occur following the first infusion. [3]

Contents

Mechanism of action

In individuals with asthma, Siglec-8 expression is increased on the surface of eosinophils and mast cells in sputum. [4] Lirentelimab depletes eosinophils via antibody-dependent natural killer cell mediated cytotoxicity.

Indications

As of 2023, lirentelimab has no approved indications. [5]

Pharmacology

Lirentelimab is a humanized, nonfucosylated IgG1 monoclonal antibody that targets Siglec-8. [6] Siglec-8 is an inhibitory receptor present on eosinophils and mast cells, with low level expression on basophils. [2] [7] Interleukin-5, granulocyte-macrophage colony stimulating factor, and interleukin-33 enhance anti-Siglec-8 mediated destruction of eosinophils. [7] Lirentelimab inhibits mast cells' IgE-mediated degranulation and de novo synthesis of prostaglandin D2 in vitro. [7]

Adverse events

Mild-to-moderate infusion reactions may occur with lirentelimab, which tend to occur following the first infusion only. [3]

Research

Lirentelimab has been studied for the treatment of chronic spontaneous urticaria, indolent systemic mastocytosis, and severe allergic conjunctivitis. [6]

Related Research Articles

<span class="mw-page-title-main">Eosinophil</span> Variety of white blood cells

Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply.

<span class="mw-page-title-main">Eosinophilia</span> Blood condition

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

<span class="mw-page-title-main">Basophil</span> Type of white blood cell

Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte and how they work is not fully understood. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They also produce compounds that coordinate immune responses, including histamine and serotonin that induce inflammation, and heparin that prevents blood clotting, although there are less than that found in mast cell granules. Mast cells were once thought to be basophils that migrated from the blood into their resident tissues, but they are now known to be different types of cells.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

Omalizumab, sold under the brand name Xolair, is a medication to treat asthma, nasal polyps, and urticaria (hives).

Interleukin 5 (IL-5) is an interleukin produced by type-2 T helper cells and mast cells.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

<span class="mw-page-title-main">Interleukin 13</span> Protein and coding gene in humans

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.

<span class="mw-page-title-main">Eosinophilic esophagitis</span> Allergic inflammatory condition of the esophagus

Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus that involves eosinophils, a type of white blood cell. In healthy individuals, the esophagus is typically devoid of eosinophils. In EoE, eosinophils migrate to the esophagus in large numbers. When a trigger food is eaten, the eosinophils contribute to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartburn.

Reslizumab is a humanized monoclonal antibody against human interleukin-5 (IL-5). Reslizumab binds specifically to IL-5, a key cytokine responsible for the differentiation, maturation, recruitment and activation of human eosinophils. By binding to human IL-5, it blocks its biological function; consequently survival and activity of eosinophils are reduced. The benefits with reslizumab are its ability to reduce the exacerbation rate and improve lung function and asthma-related quality of life in patients with severe eosinophilic asthma and with at least one previous asthma exacerbation in the preceding year. The most common side effects are increased blood creatine phosphokinase, myalgia and anaphylactic reactions.

Mepolizumab, sold under the brand name Nucala by GlaxoSmithKline, is a humanized monoclonal antibody used for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis, and hypereosinophilic syndrome (HES). It recognizes and blocks interleukin-5 (IL-5), a signalling protein of the immune system.

Siglecs(Sialic acid-binding immunoglobulin-type lectins) are cell surface proteins that bind sialic acid. They are found primarily on the surface of immune cells and are a subset of the I-type lectins. There are 14 different mammalian Siglecs, providing an array of different functions based on cell surface receptor-ligand interactions.

<span class="mw-page-title-main">CD22</span> Lectin molecule

CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.

<span class="mw-page-title-main">CD33</span> Mammalian protein found in Homo sapiens

CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.

<span class="mw-page-title-main">Eosinophilic gastroenteritis</span> Medical condition

Eosinophilic gastroenteritis, also known as eosinophilic enteritis, is a rare and heterogeneous condition characterized by patchy or diffuse eosinophilic infiltration of gastrointestinal (GI) tissue, first described by Kaijser in 1937. Presentation may vary depending on location as well as depth and extent of bowel wall involvement and usually runs a chronic relapsing course. It can be classified into mucosal, muscular and serosal types based on the depth of involvement. Any part of the GI tract can be affected, and isolated biliary tract involvement has also been reported. The stomach is the organ most commonly affected, followed by the small intestine and the colon.

<span class="mw-page-title-main">Eosinophil cationic protein</span> Mammalian protein found in Homo sapiens

Eosinophil cationic protein (ECP) also known as ribonuclease 3 is a basic protein located in the eosinophil primary matrix. In humans, the eosinophil cationic protein is encoded by the RNASE3 gene.

<span class="mw-page-title-main">SIGLEC8</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 8 is a protein that in humans is encoded by the SIGLEC8 gene. This gene is located on chromosome 19q13.4, about 330 kb downstream of the SIGLEC9 gene. Within the siglec family of transmembrane proteins, Siglec-8 belongs to the CD33-related siglec subfamily, a subfamily that has undergone rapid evolution.

The following outline is provided as an overview of and topical guide to immunology:

<span class="mw-page-title-main">Eosinophilic bronchitis</span> Medical condition

Eosinophilic bronchitis (EB) is a type of airway inflammation due to excessive mast cell recruitment and activation in the superficial airways as opposed to the smooth muscles of the airways as seen in asthma. It often results in a chronic cough. Lung function tests are usually normal. Inhaled corticosteroids are often an effective treatment.

<span class="mw-page-title-main">SIGLEC6</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 6 is a protein that in humans is encoded by the SIGLEC6 gene. The gene was originally named CD33L (CD33-like) due to similarities between these genes but later became known as OB-BP1 due to its ability to bind to this factor and, finally, SIGLEC6 as the sixth member of the SIGLEC family of receptors to be identified. The protein has also been given the CD designation CD327.

References

  1. "Lirentelimab". KEGG Drug Database.
  2. 1 2 Dellon ES, Peterson KA, Murray JA, Falk GW, Gonsalves N, Chehade M, et al. (October 2020). "Anti-Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis". The New England Journal of Medicine. 383 (17): 1624–1634. doi:10.1056/NEJMoa2012047. PMC   7600443 . PMID   33085861.
  3. 1 2 Young A (October 29, 2019). "Therapeutic antibody effective in eosinophilic gastritis". Healio. Retrieved 14 December 2020.
  4. Kerr SC, Gonzalez JR, Schanin J, Peters MC, Lambrecht BN, Brock EC, et al. (August 2020). "An anti-siglec-8 antibody depletes sputum eosinophils from asthmatic subjects and inhibits lung mast cells". Clinical and Experimental Allergy. 50 (8): 904–914. doi:10.1111/cea.13681. hdl: 1854/LU-8706271 . PMC   7610812 . PMID   32542913. S2CID   219702648.
  5. Dellon, ES; Spergel, JM (January 2023). "Biologics in eosinophilic gastrointestinal diseases". Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 130 (1): 21–27. doi:10.1016/j.anai.2022.06.015. PMID   35738437.
  6. 1 2 Johal KJ, Saini SS (October 2020). "Current and emerging treatments for chronic spontaneous urticaria". Annals of Allergy, Asthma & Immunology. 125 (4): 380–387. doi:10.1016/j.anai.2019.08.465. PMC   7056515 . PMID   31494233.
  7. 1 2 3 Youngblood BA, Brock EC, Leung J, Falahati R, Bryce PJ, Bright J, et al. (2019). "AK002, a Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody that Induces Antibody-Dependent Cell-Mediated Cytotoxicity against Human Eosinophils and Inhibits Mast Cell-Mediated Anaphylaxis in Mice". International Archives of Allergy and Immunology. 180 (2): 91–102. doi: 10.1159/000501637 . PMC   6878738 . PMID   31401630.