immunosuppressive monoclonal antibodies (mAbs)

see also:

• immunosuppressants
• innate immunity
• adaptive immunity
• chemotherapy for cancers

• immunosuppressive monoclonal antibodies are a subset of monoclonal antibodies which target specific proteins on the T-lymphocyte or B-lymphocyte surface to result in immune suppression
• they were initially designed to reduce transplant rejection and treat non-Hodgkin lymphoma but their utility has been widened to cover auto-immune diseases and other conditions
• initial mAbs were derived from mice and had issues with immune reactivity but current ones are humanized or completely human
• approval dates below are US FDA approvals

• examples:
  • Sutimlimab - used to Rx cold agglutinin disease

• examples:
  • Eculizumab
    • inhibits the formation of the membrane attack complex and preventing cell lysis and death
    • used to Rx paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome
    • approved 2007
  • Ravulizumab
    • approved 2018; used to Rx paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome

• reactivation of latent tuberculosis (TB) infection is well recognized as an adverse event associated with anti-TNF-α therapy
• examples:
  • Infliximab/chimeric A2
    • binds and neutralizes TNF-α and induces apoptosis in active T-cells
    • initially approved for use in treating Crohn disease, infliximab has since been approved for use in ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and plaque psoriasis
  • Adalimumab/D2E7
  • Certolizumab pegol - may have higher risk of serious infections than others in this group
  • Golimumab

• examples:
  • Omalizumab
    • anti-IgE agent which appears to reduce seasonal peaks in exacerbations in inner city children with asthma ¹⁾

• examples:
  • Fontolizumab
  • Emapalumab
    • approved 2018 for Rx haemophagocytic lymphohistiocytosis

• examples:
  • Fresolimumab
  • Metelimumab
  • Lerdelimumab

• examples:
  • Canakinumab

• examples:
  • Pascolizumab

• used to Rx hypereosinophilic syndrome (HES)
• examples:
  • Benralizumab
  • Mepolizumab

• examples:
  • Siltuximab - approved in 2014 to Rx Castleman disease as this is associated with overproduction of IL-6

• examples:
  • Briakinumab
  • Ustekinumab

• examples:
  • Secukinumab

• examples:
  • Bertilimumab

• IL-6 exerts its immunomodulatory effects by enhancing T-cell activation and differentiation by upregulating IL-2 receptors and IL-2 production, inducing thymocyte proliferation and thymic T-cell development, stimulating B-cell proliferation, and activating acute-phase protein production
• examples:
  • Tocilizumab
    • inhibits IL-6-mediated signalling, approved in 2010 to Rx rheumatoid arthritis
  • Atlizumab

• examples:
  • Siplizumab

• examples:
  • Otelixizumab
  • Teplizumab
  • Visilizumab

• examples:
  • Clenoliximab
  • Keliximab
  • Zanolimumab

• examples:
  • Zolimomab aritox

• leukocyte function-associated antigen 1 (LFA-1) serves as an adhesion molecule in the communication between antigen-presenting cells and T-lymphocytes
• examples:
  • Efalizumab
    • initially approved for the treatment of psoriasis in 2003 but withdrawn in 2009, owing to an increased risk of PML

• examples:
  • SAR-3419

• selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity
• CD20 is a transmembrane calcium channel implicated in B cell activation, proliferation, and differentiation
• present on the surface of B cells in the late pre-B cell through mature memory B cell stages
• due to the maintenance of antibody production by plasma cells, administration of anti-CD20 mAbs almost completely depletes peripheral B cells, but antibody levels are not dramatically reduced, suggesting that the clinical benefits of this type of B cell depletion therapy may stem from the loss of other prominent B cells functions such as antigen presentation, production of inflammatory cytokines, activation of T cells, and creation of ectopic lymphoid follicles
• initially developed to to achieve B cell depletion and treat B cell proliferative disorders, including non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL).
• use now expanded for conditions such as rheumatoid arthritis, systemic lupus erythematosus (SLE), pemphigus, multiple sclerosis (MS) ²⁾
• 1st gen: rituximab, is a murine–human chimera to which many patients develop antibodies and/or experience infusion-related reactions
• 2nd gen:
  • the humanized versions:
    • ocrelizumab
    • obinutuzumab approved 2013 for Rx CLL and in 2016 for CD-20 positive follicular lymphoma
    • ofatumumab - withdrawn 2019 for commercial reasons
    • ublituximab - 2023, approved for Rx of relapsing multiple sclerosis
    • veltuzumab
  • fully human: ofatumumab

• CD22 is not present on immature B-cells or plasma cells, but is expressed on certain differentiating B-cells
• examples:
  • Epratuzumab
    • originally developed for the treatment of non-Hodgkin lymphoma, but has since been used to treat a variety of autoimmune inflammatory disorders such as systemic lupus erythematosus (SLE)
  • Inotuzumab
  • Moxetumomab pasudotox

• examples:
  • Lumiliximab

• examples:
  • Daclizumab
    • first introduced in 1998 for Mx of transplants but discontinued in the USA in 2009, owing to the availability of more popular alternatives
  • Basiliximab
    • used for liver transplant patients since a study in 1997

• examples:
  • Brentuximab

• examples:
  • Gemtuzumab - withdrawn in 2010 because of severe veno-occlusive disease
  • Lintuzumab

• examples:
  • Dacetuzumab

• examples:
  • Natalizumab
  • Vedolizumab

• CD52 is a membrane glycoprotein of unknown function that is especially highly expressed on lymphocytes (up to 5% of surface antigens), explaining the powerful immunodepleting effect of anti-CD52 antibodies
• examples:
  • Alemtuzumab/Campath-1H

• examples:
  • Lorvotuzumab mertansine

• examples:
  • Aselizumab

• examples:
  • Galiximab

• examples:
  • Gavilimomab (murine)

• examples:
  • Ruplizumab

• examples:
  • Mogamulizumab
    • 2012 approved for use to Rx T cell lymphomas
    • approved in 2018 for relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS)

• BLyS = B-lymphocyte stimulator, a vital B-cell surface protein survival factor.
• it has has two important signalling properties: (i) preventing apoptosis; and (ii) stimulating differentiation to plasma cells.
• examples:
  • Belimumab
    • by preventing B-lymphocyte stimulator signalling, belimumab induces apoptosis and prevents immunoglobulin production

• examples:
  • Apolizumab
  • Lym-1

• activation of T-lymphocytes requires both antigen-specific (signal 1) and co-stimulatory (signal 2) pathways.
• naïve T-cells contain the CD28 receptor, to which CD80 and CD86 bind to induce the co-stimulatory signal.
• once T-cells become active, the inhibitory molecule cytotoxic T-lymphocyte antigen 4 (CTLA4) is expressed to prevent further T-cell co-stimulation.
• examples:
  • Abatacept
    • introduced 2005
  • Belatacept
    • a CTLA4–IgG fusion protein that is more specific for CD80 than Abatacept
    • proved itself as a calcineurin inhibitor (CNI) replacement that does not compromise acute rejection rates

• examples:
  • Atacicept

• examples:
  • Etanercept

• leukocyte function-associated antigen 3
• examples:
  • Alefacept

• examples:
  • Rilonacept