Monoclonal antibody therapy
Major applications include cancer, autoimmune diseases, asthma, organ transplants, blood clot prevention, and certain infections.
These antibodies have: a short half-life in vivo (due to immune complex formation), limited penetration into tumour sites and inadequately recruit host effector functions.
[citation needed] Initially, murine antibodies were obtained by hybridoma technology, for which Jerne, Köhler and Milstein received a Nobel prize.
However the dissimilarity between murine and human immune systems led to the clinical failure of these antibodies, except in some specific circumstances.
Major problems associated with murine antibodies included reduced stimulation of cytotoxicity and the formation of complexes after repeated administration, which resulted in mild allergic reactions and sometimes anaphylactic shock.
[3] The heavy and light chains of human IgG proteins are expressed in structural polymorphic (allotypic) forms.
[22] Basiliximab and daclizumab inhibit IL-2 on activated T cells and thereby help preventing acute rejection of kidney transplants.
[citation needed] Alzheimer's disease (AD) is a multi-faceted, age-dependent, progressive neurodegenerative disorder, and is a major cause of dementia.
In the case of AD, immunotherapy is believed to inhibit Aβ-oligomerization or clearing of Aβ from the brain and thereby prevent neurotoxicity.
[24] However, anti-Aβ vaccines can promote antibody-mediated clearance of Aβ plaques in transgenic mice models with amyloid precursor proteins (APP), and can reduce cognitive impairments.
[23] Vaccines can stimulate the immune system to produce its own antibodies, in the case of Alzheimer's disease by administration of the antigen Aβ.
In mice expressing APP, both active and passive immunization of anti-Aβ antibodies has been shown to be effective in clearing plaques, and can improve cognitive function.
[25] Several clinical trials using passive and active immunization have been performed and some are on the way with expected results in a couple of years.
Examples of important mAb drugs that have been or are under evaluation for treatment of AD include Bapineuzumab, Solanezumab, Gautenerumab, Crenezumab, Aducanemab, Lecanemab and Donanemab.
Phase II clinical trials of Bapineuzumab in mild to moderate AD patients resulted in reduced Aβ concentration in the brain.
However, in patients with increased apolipoprotein (APOE) e4 carriers, Bapineuzumab treatment is also accompanied by vasogenic edema,[28] a cytotoxic condition where the blood brain barrier has been disrupted thereby affecting white matter from excess accumulation of fluid from capillaries in intracellular and extracellular spaces of the brain.
However, Aβ concentration did not significantly change, along with other AD biomarkers, including phospho-tau expression, and hippocampal volume.
Phase III clinical trials of Solanezumab failed as it did not show effect on cognitive decline in comparison to placebo.
[33][34] The phase 3 clinical trials also reported infusion related reactions, amyloid-related imaging abnormalities and headaches as the most common side effects of Lecanemab.
In July 2023 the FDA gave Lecanemab full approval for the treatment of Alzheimer's Disease [35] and it was given the commercial name Leqembi.
Passive anti-Aβ mAb treatment can be used for preventive attempts to modify AD progression before it causes extensive brain damage and symptoms.
[26] DIAN-TU, launched in December 2012, focuses on young patients positive for genetic mutations that are risks for AD.
To limit radiation exposure, murine antibodies were chosen, as their high immunogenicity promotes rapid tumor clearance.
Liposomes can carry drugs or therapeutic nucleotides and when conjugated with monoclonal antibodies, may be directed against malignant cells.
Immunoliposomes have been successfully used in vivo to convey tumour-suppressing genes into tumours, using an antibody fragment against the human transferrin receptor.
Myelomonocytic and tumor cells can up-regulate expression of PD-L1, partly driven by hypoxic conditions and cytokine production, such as IFNβ.
[38] The first FDA-approved therapeutic monoclonal antibody was a murine IgG2a CD3 specific transplant rejection drug, OKT3 (also called muromonab), in 1986.
