APC Activator

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APC Activators (or Antigen-presenting cell activators) are a type of immunotherapy which leverages antigen-presenting cells (APCs) to drive an adaptive immune response. [1] [2] [3] [4] APC Activators are agonists to APC surface-expressed ligands that, when bound, induce the maturation and activation of APCs. Professional antigen-presenting cells – including dendritic cells, macrophages, and B cells – serve an indispensable role in the adaptive immune response through their unique ability to phagocytose, digest, and present exogenous (circulating) antigens to T cells, facilitating antigen-specific immune responses. [5]

Contents

Background

Professional APCs express MHC class II and CD40 molecules as surface receptors, and can be activated through direct interactions with T cells expressing these receptors' corresponding ligands, LAG-3 and CD40-L, respectively. [5] A third class of receptors that can activate APCs are called toll-like receptors (TLRs); these receptors bind foreign ligands which are structurally conserved molecules from microbes, called pathogen-associated molecular patterns (PAMPs). [6]

Therapeutic potential

Combinatorial approaches that target multiple aspects of the cancer immunity cycle, including APC activation, are promising strategies for the treatment of diseases, including numerous types of cancer. [7] Interest in the clinical use of TLR and CD40 agonistic antibodies in immuno-oncology wavered in the past decade. [6] [8] The APC Activator IMP321 (Eftilagimod alpha), a soluble LAG-3 fusion protein, is currently undergoing clinical trials in combination with chemotherapy (paclitaxel), or immune checkpoint inhibitors, including the PD-1 monoclonal antibody pembrolizumab, to accelerate the adaptive immune response in several tumor indications. [9] [2] [4]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

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

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals, including marsupials B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Memory B cell</span> Cell of the adaptive immune system

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

<span class="mw-page-title-main">CD154</span> Protein-coding gene in humans

CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40, α5β1 integrin and integrin αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells. On TFH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication. A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome. Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.

CD70 is a protein that in humans is encoded by CD70 gene. CD70 is also known as a ligand for CD27.

In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. The word "adjuvant" comes from the Latin word adiuvare, meaning to help or aid. "An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens."

<span class="mw-page-title-main">Toll-like receptor 10</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 10 is a protein that in humans is encoded by the TLR10 gene. TLR10 has also been designated as CD290 . TLR10 has not been extensively studied because it is a pseudogene in mice, though all other mammalian species contain an intact copy of the TLR10 gene. Unlike other TLRs, TLR10 does not activate the immune system and has instead been shown to suppress inflammatory signaling on primary human cells. This makes TLR10 unique among the TLR family. TLR10 was thought to be an "orphan" receptor, however, recent studies have identified ligands for TLR10 and these include HIV-gp41. Ligands for TLR2 are potential ligands for TLR10.

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

B-cell maturation antigen, also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is a protein that in humans is encoded by the TNFRSF17 gene.

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span>

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

Frédéric Triebel is a French immunologist who is best known for his 1990 discovery of the LAG3 immune control mechanism. Triebel worked through the 1990s in a collaboration between Institut Gustave Roussy and Merck Serono to establish LAG-3's mechanism of action in T cells and dendritic cells. In 2001 he founded Immutep SA, a biotech company, to develop the therapeutic potential of LAG3. In 2014 this company was acquired by Prima BioMed, where Triebel remains Chief Scientific and Medical Officer.

Eftilagimod alpha is a large-molecule cancer drug being developed by the clinical-stage biotechnology company Immutep. Efti is a soluble version of the immune checkpoint molecule LAG-3. It is an APC Activator used to increase an immune response to tumors, and is administered by subcutaneous injection. Efti has three intended clinical settings:

<span class="mw-page-title-main">Immune checkpoint</span> Regulators of the immune system

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.

References

  1. ↑ "Immutep Activities Report (ASX Announcement)" (PDF). Immutep Ltd. January 29, 2020. Retrieved February 19, 2020.
  2. 1 2 "LAG-3 – Regulating the Immune System | Immutep". www.immutep.com. Retrieved 2020-02-19.
  3. ↑ W, Kratky; C, Reis e Sousa; A, Oxenius; R, Spörri (2011-10-18). "Direct Activation of Antigen-Presenting Cells Is Required for CD8+ T-cell Priming and Tumor Vaccination". Proceedings of the National Academy of Sciences of the United States of America. 108 (42): 17414–9. Bibcode:2011PNAS..10817414K. doi:10.1073/pnas.1108945108. PMC   3198339 . PMID   21987815.
  4. 1 2 "Immutep (ASX.IMM) Presentation, Immutep TACTI-002 Clinical Results & Update Global Webcast, February 2020". www.finnewsnetwork.com.au. Retrieved 2020-03-01.
  5. 1 2 Hughes, Catherine E.; Benson, Robert A.; Bedaj, Marija; Maffia, Pasquale (2016). "Antigen-Presenting Cells and Antigen Presentation in Tertiary Lymphoid Organs". Frontiers in Immunology. 7: 481. doi: 10.3389/fimmu.2016.00481 . ISSN   1664-3224. PMC   5097899 . PMID   27872626.
  6. 1 2 Anwar, Muhammad Ayaz; Shah, Masaud; Kim, Jason; Choi, Sangdun (October 21, 2018). "Recent clinical trends in Toll‐like receptor targeting therapeutics". Medicinal Research Reviews. 39 (3): 1053–1090. doi:10.1002/med.21553. ISSN   0198-6325. PMC   6587958 . PMID   30450666.
  7. ↑ Chen, Daniel S.; Mellman, Ira (2013-07-25). "Oncology meets immunology: the cancer-immunity cycle". Immunity. 39 (1): 1–10. doi: 10.1016/j.immuni.2013.07.012 . ISSN   1097-4180. PMID   23890059.
  8. ↑ "BG9588 (Anti-CD40L Antibody) to Treat Lupus Nephritis - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-02-19.
  9. ↑ Dirix, Luc; Triebel, Frédéric (June 2019). "AIPAC: a Phase IIb study of eftilagimod alpha (IMP321 or LAG-3Ig) added to weekly paclitaxel in patients with metastatic breast cancer". Future Oncology (London, England). 15 (17): 1963–1973. doi:10.2217/fon-2018-0807. ISSN   1744-8301. PMID   30977393.
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