Mixing and matching is Nature's plan to combine and recast DNAs constantly in the search for a better set of chromosomes. We, humans, are a race characterized by diverse qualities and should understand that our presence is temporary, and in the end, only the genetic material will be left behind. Immunity is a complex process and numerous agents are involved. There is innate immunity, adaptive immunity, and passive immunity. Leucocytic phagocytosis, T or B-cell mediated cell destruction and complement activation are pathways by which the immune system works. Everyone is born with a level of innate immunity or a generalized level of protection which helps the organism to tide over an insult.
There is active immunity and passive immunity. Passive immunity is short-lasting. This is either injection-induced or "borrowed". Adaptive immunity is learned and acquired as one age and experiences new insulting situations. The concept of active immunity is complex. Both adaptive immunity and any outside concentration of antibodies that are capable of eliciting an immune reaction are considered capable of inciting active immunity.
Metchnikoff and Ehrlich were awarded the Nobel Prize and are considered the founding fathers of immunology. They were aware of innate immunity only and were interested in enhancing its effects. Metchnikoff theorized and established phagocytic destruction as an immunological attempt at destroying the invader not identified as self. Later other agents were discovered. Antibodies in the body are special types of proteins in the system that can bind to invading agents or pathogens like bacteria, viruses, parasites, etc, in such a manner so that the complex can no longer be identified by self and is destroyed as unnecessary. Structurally the antibody molecules have a Y-shaped structure, with two heavy and two light chains. There are specific sites where the so-called offending agents can bind -- the Fab and the Fc regions. Moreover, the antibody molecules have a variable and a constant region -- the constant region remaining the same for all such molecules. The subtle changes in the variable zones make a particular type of antibody unique. Antigens, on the other hand, are complex three-dimensional structures with specific binding sites on the surface for antibodies, the epitopes. Usually, multiple antibodies attach to designated epitopes forming an unrecognizable complex.
The role of white blood cells in immunity has been a debated issue since immunity came to be recognized. The neutrophils are commonly found in pus, other inflammatory debris, and similar situations. They are mainly responsible for phagocytic activity in an attempt to remove injurious elements from the site of the attack. Antigens, the injurious elements, are usually complex structures and can cause harm. The antibodies are efficient in identifying this threat and multiply in numbers to overwhelm the invading antigen. If a host organism is exposed to an antigen, the host will develop an array of antibodies that each binds to a separate epitope, so these antibodies will vary in specificity and fight against the antigen more efficiently. This highly specific binding activity is the mainstay of immunogenic self-protection. They are also called granulocytes, as a testimony to the microscopic granular appearance, and multiply significantly when they are presented with allergic antigens. The increase in the number of basophils and eosinophils is diagnostic. The large macrophages are the first to respond in an adverse situation. There are many cells with phagocytic behaviour, and they tend to be the M1 type (when classically activated) or M2 (when alternatively activated). These are large white blood cells that by their phagocytic activity break down and present to other cells for total annihilation.
The lymphocytes come next. These can be a B lymphocyte or a T lymphocyte. The B- B-lymphocytes are specific and programmed to form a particular gamma globulin. First, a large plasma cell is produced when the B cell encounters an antigen. A large number of gamma globulin antibodies are created which attach themselves to the epitope moiety of the antigens and form large inadmissible complexes or break them down into smaller molecules that can be tackled by other cells. The specific interlocking and creation of the antibody-antigen complex, akin to key matching a lock, programs this complex to eventual destruction. The T-lymphocytes are complex. Some T-cells kill or annihilate as soon as they are presented with an antigen. Other T-cells designate and signal other cell types to form cytokines and lymphokines, which eventually destroy antigenic material. The cytokines and lymphokines are transient and in addition to their destructive power, are the intra-cellular chemical messengers (signalling proteins) triggering the creation of more such products. The immune response is a coordinated and communicated system where individual cell lines not only perform their designated work but also are responsible for signalling and assuming other roles so that an insult can be averted. There are many antibodies, and the IgG group is an example. Similarly, cytokines may be in different forms ---- the interleukin, interferon, tumour necrosis factor, colony-stimulating factor, epidermal growth factor, etc., are examples. The moot point is immunity is the organism's way of countering insult.
The term monoclonal antibodies, as the name suggests, is based on the clonality, or the state of a cell or substance derived and generating a single layer line. Mono is the prefix used to imply single and the phrase monoclonal antibody is used for terms used in immunity. The term becomes self-explanatory and the acronyms MAB, maB, or Mab have been used at various times to indicate monoclonal antibodies.
Since the basic understanding of the immunity process, the thought had been on targeting and killing cancer cells by the same immunological principles. It was Paul Ehrlich (in the 1900s) who suggested the concept of a "magic bullet" or "zauberkugel" where a compound was created to specifically target the offenders, mainly the cancer cells. Later in the 1970s with recognition of B-cell multiple myeloma para-proteins or monoclonal antibodies were studied. Simply speaking these man-made agents are produced in the laboratory by first injecting a mouse with an antigen and then the antibody so produced in the mouse is harvested, by the complex hybridoma method. The immune cells are cloned or made to mimic or generate from similar human immune cells, and the antibody is produced in response. Further on mouse hybridomas were developed and monoclonal antibodies were created. These hybridomas were cultured in a special medium and then from the resultant enriched ascitic fluid so produced an agent extracted by serial purification and ultra-filtration or dialysis. These were the monoclonal antibodies. Humanized applications of such agents were targeted as soon as the notion came into effect. Chemicals were developed and used as drugs with specific action, binding and inactivating targets with faulty functions. It was found that these agents were capable of reversing the ill-effect of many less understood conditions and thus its role in invasive malignancies where metastatisation and morbid surgery were a rule.
Monoclonal antibodies are considered to be the greatest advances in biomedical research. The researchers always targeted the creation of a complex medicinal agent capable of treating a condition, where, the drug portion is attached to a platform agent that is naturally present and can reach the area of interest. This mainly helps in selective portability allowing the drug to act in the pathological area hitherto inaccessible to the active medicine.
The first monoclonal antibody introduced in the market was Orthoclone-muromonab-CD3 better known as OKT3. It was used for preventing transplant rejection and has the same use and efficacy as before. The market has been flooded with several monoclonal antibodies and they are mainly used in specific cancers with acceptable and comparable, if not better, results to surgery and other forms of treatment. Commonly used monoclonal antibodies include:
Rituximab is one of the commonest monoclonal antibodies. It is used as an anti-cancer medication and is effective against several autoimmune conditions. Action has been noted against Non-Hodgkin lymphoma, used for non-Hodgkin lymphoma, chronic lymphocytic leukaemia in non-geriatric patients, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow injection into a vein. Biosimilars of Rituximab include Blitzima, Riabni, Ritemvia, Rituenza Rixathon, Ruxience, and Truxima.
Adalimumab (Humira, Amjevita) - Antirheumatic medicine.
Abciximab (ReoPro) - is an inhibitor of platelet aggregation.
Alefacept (Amevive) - or ustekinumab is used for immunosuppression in psoriasis.
Alemtuzumab (Campath) - has use in chronic lymphocytic leukaemia and may be used, when all other treatment options fail, in multiple sclerosis.
Basiliximab (Simulect) - induction immunosuppression in transplant surgery.
Belimumab (Benlysta) - used in systemic lupus erythematosus.
Bezlotoxumab (Zinplava) - prevention of recurrence of Clostridium difficile infections.
Canakinumab (Ilaris) - This agent is used for the treatment of systemic idiopathic juvenile arthritis and active Still's disease. It targets interleukin beta1 to alleviate the inflammatory symptoms of these conditions.
Certolizumab pegol (Cimzia) - This monoclonal antibody has multifarious action and targets the tumour necrosis factor-alpha. Commonly used to minimize symptoms in patients with Crohn's disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and similar autoimmune conditions.
Cetuximab (Erbitux) - Cetuximab is an epidermal growth factor receptor inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer.
Daclizumab (Zenapax, Zinbryta) - Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor of T-cells, and finds an application in Crohn's disease.
Denosumab (Prolia, Xgeva) - Denosumab is a human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumours of bone. A normal serum Calcium level is essential.
Efalizumab (Raptiva) - A once-weekly s/c injectable recombinant monoclonal antibody recommended mainly for psoriasis and its complications.
Golimumab (Simponi, Simponi Aria) - also has several indications and is capable of giving symptomatic relief in autoimmune conditions like rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriasis, etc. It, similar to certolizumab, targets TNF alpha and causes a profound reduction of inflammatory markers.
Inflectra (Remicade) - commonly known as infliximab, is indicated for the control of intestinal autoimmune conditions like Crohn's disease and ulcerative colitis. It is also effective against autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, and psoriasis. Behçet's disease responds to this drug.
Ipilimumab (Yervoy) - another welcome anticancer medicine mainly indicated for managing advanced melanomas where other treatment forms are not effective. The effect on lung malignancies (NSCLC and SCLC), bladder, and prostatic cancer is still under trial.
Regeneron is a company that came into prominence by injecting a mixture of monoclonal antibodies into then-US President Donald Trump when he became RTPCR-free for COVID-19. Regeneron or the Eli Lilly preparation, both of which received FDA approval, are combinations of two monoclonal antibodies like casirivimab and indemivimab and are indicated in high-risk individuals within 3-7 days of contracting the disease. Clinical trials, though positive, are limited as the number is not high. There also has been a clinical trial comparing vaccination results. Both are not cent-% foolproof and the cost of mass vaccination in the general population is lower.
The monoclonal antibodies are not the ideal agents, and these are not without complications. First of all, these have a large molecular size. These may not reach the site of the intended action. Secondly, these being proteins themselves, these can incite or precipitate an allergic reaction. Even a cytokine storm is theoretically possible. The monoclonal antibodies are highly specific and a slight modification of the epitope or the binding site makes them ineffective. The high price of a monoclonal antibody precludes its use. The recent interest is in the nano portability of drugs. The application of nanotechnology for drug delivery provides the potential for enhanced treatments with targeted delivery and fewer side effects. This is technology-based where nano-materials are used to improve the penetrability of drugs that were poorly available at the place where needed. There was a noticeable increase in the potency of the materials when miniaturized and the following advantages were noted:
Specific targeting to reduce drug accumulation within healthy tissue.
Help retain the drug in the body long enough for effective treatment.
The extension of drug bioactivity through protection from the biological environment.
Allow for the transportation of drugs across epithelial and endothelial barriers.
Combined therapeutic and diagnostic modalities into one agent.
The property of Enhanced Permeability and Retention Effect (EPR) enables such agents to work more efficiently and without ill effects. The use of nanomaterials in the biomedical world has now become a reality and other than drug delivery, there are several applications implicating the utilization of nano-dimensional materials including nano-sensors and nano-robots for diagnosis, delivery, and sensory purposes, and actuate materials in live cells. A nano-particle-based method has been developed which combines both the treatment and imaging modalities of a cancer diagnosis. The very first generation of nanoparticle-based therapy included lipid systems like liposomes and micelles, which are now FDA-approved. These liposomes and micelles can contain inorganic nanoparticles like gold or magnetic nanoparticles. The bioavailability is substantially more and the ability to penetrate places not accessible till now makes nano-fabricated small-sized materials even more desirable. Also, an increase in potency of the active drug portion is seen. So far extensive research is going on with the nano-materials, especially in the field of treatment of malignancies.
Research on nano-drugs does not mean the end of the road for monoclonal antibodies. In certain situations, they are still the best and the only available options. More useful target-oriented products are on the horizon and a place for monoclonal antibodies will always be there.
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