(Selected Tables and Figures referenced, but not present in this blog
can be found in their corresponding Science Version blogs)
Among all the topics discussed in these blogs, the next three (immunotherapies, cancers, and infectious diseases) will probably be out of date sooner than all the others, and that’s good. The research in these three areas is undoubtedly the most prolific and productive in all of the medical biosciences. So, while we’ll try to give the most recent information, consider these following discussions more baseline (circa 2023) than the most recent science. As we continue this blog (hopefully for years to come), updates on these 3 areas will be the principal focus of our discussions (hopefully from the researchers involved. This blog has already been updated to July 2023 by Marjorie A. Shapiro, Ph.D., Chief, Laboratory of Molecular and Developmental Immunology, Division of Biotechnology Review and Research). The immunotherapeutics, i.e., pharmacologic agents that modulate the immune system), do so by targeting the cells, chemicals and biological processes occurring in chronic inflammation (CI). These processes include those involved in autoimmune diseases (localized and diffuse), cancers and the wide range of other CI-related diseases. The basis of immunotherapies is to utilize the chemicals, molecules and proteins of the immune system, the ones we’ve been talking about in all the previous blogs (Table 4.2), to elicit desired therapeutic effects by immunomodulation, meaning amplifications, supplementation or suppression of the chemical and molecular components identified in the inflammatory cascade, the adaptive immune response precipitating the inflammatory phenomenon from back in Blog #9.
Biosimilars and small molecule drugs
The immunotherapies are generally considered “non-specific” therapies, that means they can have multiple therapeutic effects by targeting the biological processes in diseases. These non-specific therapies are subdivided into monoclonal antibodies, therapeutic proteins, biologics, small molecule drugs, and sometimes collectively referred to as "biosimilars. For example, Truxima is a biosimlar for rituximab. An additional brand name for blinatumomab is Blincyto. There are also approved biosimilars for the monoclonal antibodies adalimumab and infliximab.
Small molecule drugs also have elicited the generation of biosimilars. These include molecules that target kinases (a type of enzyme or protein that speeds up chemical reactions in the body). The kinase inhibitors Tofacitinib, baricitinib and oclacitinib are approved for autoimmune indications and baricitinib is also approved for COVID patients who need supplemental oxygen. Others approved biosimilars include adalimumab and infliximab but some kinase inhibitors are not yet FDA approved. There are also several BTK (Bruton tyrosine kinase) inhibitors approved to treat B cell malignancies, but none yet for autoimmune diseases.
Monoclonal antibodies
Sometimes the actual cells and chemicals involved in a bodily process are used to supplement the body’s own defense mechanisms. Monoclonal antibodies (any drug with the suffix, “… mab” in the generic name, most listed in Tables 5.4 and 5.5) are laboratory antibodies or even the patients’ own antibodies, bioengineered and used to mimic the immune system’s own antibody response to a specific antigen and the potential autoimmune disease or CI it can produce. These antibodies are made by identical immune cells that are all replicated (cloned) from a unique parent cell from the patient. Monoclonal antibodies produced naturally by your body are classified as biologics and help the immune system recognize antigens and pathogens that cause disease. They then mark them and destroy them through the innate and adaptive immune response.
Like your body’s own antibodies, engineered monoclonal antibodies recognize specific “evil” targets and function similarly to our bodies’ natural antibodies. These engineered monoclonal antibodies are often generated by isolating or transforming antibody-producing cells taken directly from the patient or immunized animals. They then transplant the antibody-encoding genes (remember those amazing genes?) of these monoclonal (natural of engineered) cells into reproducing cell lines which generate large amounts of identical antibodies.
Checkpoint inhibitors (drug names ending in "...ib") are monoclonal antibody drugs that target and attach to certain specific proteins on T cells and some cancer cells. This binding action can inhibit those proteins and boost the immune response against cancer cells (more on this in exciting therapy in Blog #24 on cancer treatments). Outstanding researchers, especially Kohler and Milstein identified a way to clone individual B cells that make endless copies of themselves and produce a lot of a single antibody.These “cloned” monoclonal antibodies could then be categorized by which antibodies respond to which antigens (pathogens, carcinogens, etc.). From this information, immunopharmaceutical drugs have been designed with specific types of monoclonal antibodies that can attack specific identified antigens. Additional research to design and develop monoclonal antibodies changed the face of health care as monoclonal antibodies have revolutionized disease care in the 21st century. Over 100 monoclonal antibodies have been approved to treat a variety of diseases including many types of cancer, autoimmune diseases, inflammatory conditions, neurological conditions, infectious diseases, and other indications. Biologic drugs Beyond monoclonal antibody drugs or “biologic drugs” (Table 5.6) there’s an additional category termed “ DMARDs,” disease-modifying anti-rheumatic drugs. These include drugs such as hydroxychloroquine (you’ve heard of that one, I’m sure!), methotrexate, sulfasalazine, and leflunomide. This second category of biologics attempts to regulate, increase or decrease, the immune response. These nonspecific, generic biologics treat a range of autoimmune (CI) diseases by processes that act on their diseases’ biochemistry to inhibit inflammatory generating agents or promoting inhibitory agents to those inflammatory generating agents. Other popular nonspecific, biologic immunotherapeutic agents include chemicals in the adaptive immune process like cytokines, interferons, interleukins, and anti-TNFs agents, that strong proinflammatory cytokine discussed previously in Blog #15 and 16). Of course, as with corticosteroids and any immunosuppressive agents, the risk of secondary infection must always be considered. The reason for the large variety of immunotherapeutic drugs is due to the extensive diversity of chemicals (mediators) that stimulate inflammation producing chronic inflammatory and autoimmune processes. To wit, research in immunotherapeutic drugs reaches back into the chemistry of the innate and adaptive immune system as well. While the biologics include a large number of drug options, all are attempting to regulate the immune response. Each has a distinct biochemical effect on different mediators. This gives treating physicians the ability to get a maximal drug effect (and sometimes a definitive diagnosis) by “experimenting” with the response(s) to a variety of biologics. This also confuses the hell out of the public when they watch a TV commercial promoting a biologic drug for a specific autoimmune condition, e.g., rheumatoid arthritis, on one station. Then they change channels and see the same drug being promoted for an entirely different condition (e.g., Crohn’s Disease). The drugs are specific for individual chemical mediators that occur in multiple autoimmune diseases, and thus, they are nonspecific for any one disease. Make sense?
(See the Science Version, Blog #21 for July 2023 expanded and updated information on monoclonal antibodies, biologics and small molecule drugs)
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