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Tuberculosis (TB) is (still) a prominent bacterial infectious disease, causing a reported 1.6 million people to die last year. The BCG vaccine was used as a treatment for TB since the early 1900s, however, this has still failed to stop the transmission of the disease, particularly in regions that are affected by dis-proportionately high cases of tb (known as high burden areas). There are several theories around the BCGs lack of efficacy in certain areas, such as genetic variations in BCG, genetic variations in populations rendering the vaccine useless, or interference by non-tuberculous bacteria. Adults who have the pulmonary disease are particularly susceptible to the condition.
Humans have a mechanism of immunity to counter the TB virus. A 2009 study showed that the human body can cope with TB by virtue of it being converted to a latent form in the body. 90% of individuals tested were found to have a stable, controlled latent form of the disease, however, this endogenous mechanism of action is still poorly understood, meaning it can’t yet be used to create a therapeutic agent, as a vaccine for the condition. In searching for an alternative to the current vaccination approach, MVA85A vaccine has been developed. This viral therapy causes a CD4+ T cell response to T cell antigens. However, this vaccine has failed in two large-scale clinical trials to show any clinical improvement beyond what is provided by the BCG vaccine in TB treatment. A similar trend has been seen with other vaccine candidates aimed at treating TB, which has led to a search for alternative methods of treatment.
Another antibody treatment for TB being developed is known as Antibody-mediated immunity (AMI). The Mycobacterium tuberculosis (an active viral component of TB) is an intracellular pathogen. Historically, antibodies weren’t investigated as a treatment for tb due them being an intracellular pathogen, as antibodies are generally seen to possibly have a role in immune infections inactive disease states. However, even in conditions where there is no protection from vaccination with antibodies derived from the active disease state, there is a class of synthetic vaccines that cause the release of disease-resistant antibodies. These synthetic vaccines are being explored as a potential treatment to address the problem of TB.
As biotechnology develops, there are many potential treatments using antibodies for vaccine-based immunity for infectious diseases. Large monoclonal antibody libraries have been developed from cloned Human memory B-cell samples. This, along with the identification of human monoclonal antibodies (hmAbs) that work against specific disease (HIV, malaria, dengue, etc.) mean that antibodies have great potential with regards to infectious disease treatment. In Scheid’s paper, they found antibodies on conserved antibody binding sites on the gp140 protein. These antibodies found have shown some success in animal models, however, further characterization of these antibodies is necessary as there is fleeting information with regards to their activity and specificity.
Caskey et al. isolated hmAbs (3BNC117) which act as CD4+ T cell-binding sites from an HIV-1 patient and used them as a stand-alone I.V. treatment. These antibodies showed anti-infective properties. They treated both HIV-1 infected and non-infected individuals and found that it reduced the viral load and reduced viremia (increased CD4+ T-cell count) 30 days after treatment. Resistance to the antibody treatment was seen, but not on a large scale. Clinical tests have led to the conclusion that immune-compromised individuals, such as those with HIV, are more susceptible to contracting an infectious condition such as TB.
In addition, depletion of CD4+ T-Cells (a condition associated with HIV infection) results in a greater risk of contracting TB. One study, conducted in Cape Town showed that of 29478 known cases in South Africa in 2009, 87% of those were HIV-positive. 61% of those had CD4+ T-cell counts of below 200, and 83% of those had CD4+ T Cell count of below 350, compared to a normal range of between 500-1500. People with reduced expression of transcription factors such as Signal transducer and activator of transcription 1 (STAT-1) and signaling molecules such as Interleukin 2, which regulate lymphocytes and leukocytes (the cells that confer immunity) have increased susceptibility to TB also. iv Effective use of these monoclonal antibodies can act as both a direct and indirect treatment to a condition like TB. It can prevent already sick individuals (such as those with HIV) from contracting TB as they result in improved immune responses (higher CD4+ levels). If TB-specific antibodies are characterized these can be applied to TB patients in the same vein as outlined above.
Monoclonal antibodies (mAbs) derive their utility from being able to bind using one microbial binding site. mAbs utilize endogenous immunogenic processes to treat infectious diseases. They elicit immunomodulatory mechanisms, opsonization (phagocytes targeting bacterial cells), and complement dependant cytotoxicity. mAbs effectively treat hemagglutinin A influenza virus by hemagglutination inhibiting mAbs (HI-mAbs) blocking the attachment of virus particles to the cell. Non-HI mAbs were also found to inhibit viral infectivity. While they don’t inhibit attachment to the host cell receptor, they inhibit the migration of the virus past the vacuole membrane. This is achieved by a conformational change in the hemagglutinin, initiated by a response to low ph within the cell. Antibodies can also be used to treat Candida albicans, a yeast pathogen that proliferates in humans causing conditions like thrush. In Moragues et al.’s paper, it is outlined how anti- C. Albicans antibodies prevent infection through de-activation of viral enzymes, opsonization, and destruction of the viral particles. Microcidal antibodies have utility as a stand-alone treatment as well as part of combinatorial therapy.
Hepatitis C is another infectious disease that has the potential to be treated by antibodies. In theory, a poly Immunoglobulin (poly IgG) would be a suitable treatment. it would be made up of different HCV vaccines, however, this therapy is not possible due to the lack of vaccines for Hepatitis C currently. Another method of treating Hepatitis C is through the isolation of endogenous antibodies that bind HCV particles (deactivating them). They isolated the recombinant Hepatitis C glycoprotein E2A from a phage library obtained from the RNA of Hepatitis C patient. x These mAbs bind in 3 regions of the E2A protein, one of which is genetically conserved across the Hepatitis C genome. These E2A antibodies also neutralize heterologous Hepatitis C early replicates in a murine model. This trial showed the potential utility of broad-spectrum Hepatitis C antibodies. This technology could lead to the advent of a prophylactic vaccine. Vaccine development using antibodies could then lead to the development of a polyclonal treatment.
Antibodies are being investigated as a treatment for the proteinaceous-prion disease. One landmark study conducted by White et al. (2003) showed their utility. They first showed in vitro that monoclonal antibodies with low specificity for PrPsc (infected prion protein) can prevent the conversion of cellular prions (PrPc ) to PrPsc. This experiment was repeated in vivo using murine models, where they achieved similar results. The antibodies also showed the capacity to reduce PrPsc levels and the infectivity of the prion disease even after cellular prions had been exposed to the disease. The treated animals were observed to be healthy some 300 days after the mAbs were administered, while the control mice had died. Building from this, A single-domain antibody with dual specificity for both normal cellular and infected prion states was investigated by Jones et al. in 2010. They used camel-derived anti-prion antibody immunized with scrapie particles adsorbed to beads which prevented infection of vulnerable neuroblastoma N2A cells. These antibodies also showed an ability to cure scrapie-infected bacterial cell cultures. The antibody was small enough to cross the Blood-Brain Barrier which then allowed it to target cytosolic prion proteins. When compared to a conventional anti-prion antibody derived from murine models didn’t show the same capacity to inhibit replication of the infected prion particles. Additionally, the camelid antibodies showed no neurotoxic properties. This area of research, although slowly progressing could act as a primary treatment for prion disease and similar neurological conditions in the future.
In all, the use of antibodies for the treatment of infectious disease is a promising field, with current and future therapeutics in the pipeline. The use of antibody therapies deals with problems faced due to the aforementioned diseases, along with in outbreak situations, such as those in an Ebola breakout. When mass treatment of a condition is necessary, immunotherapy could be preferable to vaccines, particularly as the technology develops.
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