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A better understanding of the underlying molecular pathologies in various diseases has helped identify specific therapeutic targets for the development of monoclonal antibody (mAb) drugs. Hence, several mAb drug development also requires the co-development of molecular biomarker-based diagnostics in order to select patients who are most likely to respond.
In the last few years, there has seen an increase in the approval of antibody drugs for clinical use, mainly for cancer and auto-immune diseases. Many more are under clinical evaluation anticipating approval in the coming years. Below we discuss the disease areas where antibody therapies have demonstrated significant success.
Monoclonal antibody therapy is one of the most successful treatment strategies for cancer. Over the last two decades, several landmark drugs have been proven efficient, paving way for personalized medicine and biomarker derived treatments.
Cancer treatments using mAb drugs is achieved via various modes of action. Targeted therapy which utilizes mAbs for direct targeting of cancer cells and induction of apoptosis has been one of the most preferred therapeutic strategies. These antibody drugs can specifically bind to cells expressing tumor-specific antigens such as HER2 (Trastuzumab or Herceptin®) and CD52 (Alemtuzumab, trade name Lemtrada®), inhibit cell proliferation signaling pathways and recruit natural killer cells or complement factors. Alternatively, mAbs can be designed to target vascular and stromal components such as VEGF, VEGFR and FAP, in order to slow down tumorigenesis. For example, trade name Avastin® (anti-VEGF) can inhibit the growth of blood vessels around the tumor, thereby disrupting the tumor micro-environment and nutrient supply.
Recently, immunotherapy has emerged as a new vertical in cancer treatment after growing evidence demonstrating the immunosuppressive ability of cancer cells. Antibodies targeting immune checkpoint pathways and enabling T-cell activation, known as immune checkpoint inhibitors, have demonstrated considerable success against liquid and solid tumors in clinical trials. Ipilimumab/Yervoy® (anti-CTLA4), Nivolumab/Opdivo® (anti-PD1), and Pembrolizumab/Keytruda® (anti-PD1) are some of the first generations of approved checkpoint inhibitors.
Currently, several mAbs have been approved for therapy in cancer and many are in the clinical pipeline. The future of mAb therapeutics aims at personalized combination therapies to overcome tumor heterogeneity and improve treatment efficiency.
Autoimmune diseases are generally characterized by inflammation caused by defective elimination or regulation of self-reactive immune cells. This inflammation results in tissue injury and clinical manifestation of the disease. MAbs have revolutionized the treatment of autoimmune diseases as these can target different elements of the immune system to suppress the unrestrained responses. The mode of action of mAbs against autoimmune diseases includes blockade and depletion of T cells and/or B cells, inhibition of the interaction between T cells and antigen-presenting cells, blockade of T and B-cell recruitment, blockade of T-cell differentiation or activation, and blockade of pro-inflammatory cytokines.
Clinical data shows specific cytokines to be key players in the causation of the disease and thus inhibiting the cytokines using mAbs has shown to be an effective approach. Initial success was mostly achieved by the use of mAbs targeting TNF-α, an essential component in the inflammatory signaling cascade. While anti-TNF-α mAb alleviated rheumatoid arthritis (RA), it has also been found effective in treating other auto-immune diseases such as systemic lupus erythematosus (SLE), Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis and juvenile RA. Some of the other approved mAbs include Tocilizumab/Actemra® or RoActemra® (anti-IL-6R) for both RA and juvenile idiopathic arthritis, Rituximab/Rituxan® (anti-CD20) for RA and Alemtuzumab/Lemtrada® (anti-CD52) for multiple sclerosis. Recently, fully humanized mAbs such as Belimumab/Benlysta® (anti-BLys) and Secukinumab/Cosentyx® (anti-IL17A) has been approved for SLE and psoriasis, respectively.
The limitations of hyperimmune sera from immunized animals and human donors, such as lot-to-lot variability, risk of pathogen transmission and immunological complications have paved way for mAb therapeutics in infectious diseases. These drugs specifically target viral or bacterial proteins, interfering with the lifecycle and/or eliciting an immune response. Antibodies can also be used to neutralize toxins in bacterial infections.
Palivizumab (Synagis®) is the first mAb approved for the prevention of the severe respiratory disease caused by respiratory syncytial virus in high risk populations. This mAb targets the F-protein, and inhibits virus replication and also reduces the frequency of the condition in infants. Ibalizumab (Trogarzo®) is another promising mAb, which was approved in 2018 for the treatment of multidrug-resistant HIV-1 infection. This blocks the viral entry into the host CD4+ T cells by binding onto the CD4 receptors and thus it plays a role as a post-attachment inhibitor. Also, anti-endotoxins directed against the lipid A of gram-negative bacteria have shown favorable outcomes in treating sepsis. Currently, several other promising mAbs are under development to prevent infectious diseases caused by Ebola virus, hepatitis B and C, herpes simplex virus, among others.
Several antibodies have been repurposed for use in retinal diseases such as age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy. Anti-VEGF (Bevacizumab/Avastin®, Ranibizumab/Lucentis®) and anti-TNF-ꭤ (Infliximab/Remicade®, Adalimumab/Humira®) therapies have been quite successful in treating neovascularization and inflammation in the eye. Many other fully-human and Fc engineered antibodies against amyloid beta peptides and cytokines are currently under development for better efficacy.
Asthma is a chronic inflammation of the lower respiratory tract caused by multiple underlying pathological factors. Exacerbations can be triggered by allergens causing severe episodes. Omalizumab/Xolair® is the first mAb drug approved for severe asthma, which targets IgE and inhibits the allergic cascade. MAbs against other targets in the eosinophil maintenance pathway, such as IL-5 (Mepolizumab/Nucala®, Benralizumab/Fasenra®, and Reslizumab/Cinqaero®) and IL-4Rα (Dupilumab/Dupixent®) have also been approved, with numerous others under clinical trials.
XLH is an X-linked dominant form of rickets with a defective PHEX gene. This results in overactivity of fibroblast growth factor 23 (FGF23), leading to hypophosphatemia. Burosumab (Crysvita®) targeting FGF23 is the first-in-class drug approved for the treatment of this disease.
Migraine is characterized by severe throbbing pain which could be episodic or chronic. Calcitonin gene-related peptide (CGRP) is a vasodilator that is known to play a role in the pain process in migraines. The anti-CGRP antagonistic mAbs, Erenumab (Aimovig®), Fremanezumab (Ajovy®), and Galcanezumab (Emgality®) have been recently approved for the prevention of migraine attacks.
The extracellular accumulation of amyloid betapeptides (Aβ) has been found to be a causative factor of dementia in many neurodegenerative diseases like Alzheimer’s. Many anti-Aβ mAbs such as Solanezumab and Bapineuzumab are currently under phase II/III clinical trials.
Immunopharmacotherapy is the latest therapeutic strategy that focuses on blocking the drugs before they reach the central nervous system, rather than treating the drug effects on the brain. A fully human anti-cocaine antibody, GNCgzk, has shown promising results in clinical trials for the treatment of cocaine dependency and cocaine-induced acute toxicities. MAbs against other substances including nicotine, PCP, and methamphetamine have also demonstrated potential efficacy in animal models.
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