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topics discussed in these blogs, the next three (immunotherapies, cancers, and infectious diseases) will probably be out of date sooner than all the others, and that’s good.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 immunomodulation) target the cellular, biochemical and molecular biological processes occurring in chronic inflammation (CI) including autoimmune diseases (localized and diffuse) as well as a plethora of other CI-related diseases. The basis of immunotherapies is to utilize proinflammatory mediators (Table 4.2) to elicit desired therapeutic effects through the immunomodulation (amplifications, supplementation, suppression) of the chemical and molecular components identified in the inflammatory cascade (remember that from back in Blog #9 on the adaptive immune system?). The immunotherapies are generally considered “non-specific” therapies (immunomodulating [suppressing or stimulating] therapies) targeting the cellular, biochemical and molecular biological processes, rather than a specific disease. They can be loosely subdivided into biological drugs, such as “monoclonal antibodies” and “therapeutic proteins”, and small molecule drugs (sometimes collectively referred to as "biosimilars).
Monoclonal antibodies
Truxima is a biosimlar for rituximab. In table 5.5, the an additional brand name for blinatumomab is Blincyto. Not all the kinase inhibitors are FDA approved. Tofacitinib, baricitinib and oclacitinib are approved for autoimmune indications and baricitinib is also approved for COVID patients who need supplemental oxygen. There are several BTK (Bruton tyrosine kinase) inhibitors approved to treat B cell malignancies, but none yet for autoimmune diseases. There are also others and there are approved biosimilars for adalimumab and infliximab.
Sometimes the actual cells and chemicals (humoral agents) involved in a bodily process are used to supplement the body’s own defense mechanisms. As an example, monoclonal antibodies (any drug with the suffix, “… mAb” in the non-proprietary name list (included in Tables 5.4 and 5.5) are laboratory antibodies (or actual patients’ antibodies) engineered and used to mimic the immune system’s own antibody response to a specific antigen and its potential resultant autoimmune disease or CI. Monoclonal antibodies are classified as biologics. As regards naming of monoclonal antibodies, rules for naming mAbs have changed several times and the most recent update in 2022 finally changed the suffix. So any monoclonal antibodies that didn’t have a non-proprietary name before the new rules were in place will have one of 4 suffixes, indicating if it is a monoclonal antibody with or without an engineered Fc region, a bi- or multi-specific antibody or an antibody fragment that contains an antigen binding region.
In the US, the non-proprietary name is given by the USAN council (https://www.ama-assn.org/about/united-states-adopted-names/usan-council), which is a member of the INN, provides names used globally. In general the USAN and INN names for drugs and most biological are the same. Several below may be useful in different sections of this blog post or different blog posts. A short piece was published in the Lancet that explains the new suffixes and explains the reasons for the change (WHO/INN link to INN stems include biologics and small molecule drugs).
WHO/INN Link specific for mAbs; https://www.who.int/teams/health-product-and-policy-standards/inn/inn-bio/inn-bio-inn
WHO/INN ink for different categories of biologics (this page takes you to the mAb
page);
https://www.nature.com/articles/s41573-020-0082-8 Regarding kinase inhibitors, here is
a relatively recent review that lists many as well as mAbs and other biologics;
These antibodies are made by identical immune cells that are all clones of a unique parent cell. Monoclonal antibodies produced naturally by your body (cellular, humoral, antibodies, etc.) and help the immune system recognize antigens and pathogens that cause disease and mark them for destruction through the innate and adaptive immune response. Like your body’s own antibodies, engineered monoclonal antibodies recognize specific targets and function similarly to natural antibodies. These engineered monoclonal antibodies are often generated by isolating or transforming antibody-producing cells taken directly from immunized animals or patients, and transplanting the antibody-encoding genes of these cells into suitable producer cell lines, rather than using hybridoma technology (method for producing large amounts of identical antibodies).
Checkpoint inhibitors are a type of monoclonal antibody that target and attach to PD-1, PD-L1, and CTLA-4 proteins on T cells (and some cancer cells). This binding action can inhibit the proteins and boost the immune response against cancer cells (more on this 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 responded to which antigens (pathogens, carcinogens, etc.). From this information, immunopharmaceutical drugs were designed with monoclonal antibodies that would attack a specific identified antigen. 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.
Table 5.6
Biologic and small molecule immunotherapeutic drugs
In addition to monoclonal antibody drugs, “small molecule drugs” and other types of biological products (Table 5.6) include an immunosuppressive 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. A second category of biologics attempts to regulate (increase or decrease) the immune response. These nonspecific biologics treat a range of autoimmune (CI) diseases by processes acting on their immunopharmacology to inhibit proinflammatory agents or promote inhibitory agents biochemically. Other popular nonspecific, biologic immunotherapeutic agents include cytokines like interferons; interleukins; anti-TNFs (tumor necrosis factor, a strong proinflammatory cytokine discussed previously in Blog #15 and 16); other immune system modulators. 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 proinflammatory mediators in the 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 attempting to regulate (increase or decrease) 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., RA) 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 mediators that occur in multiple autoimmune diseases, and thus, they are nonspecific for any one disease. Make sense?
Discussion Questions:
Monoclonal antibodies, natural and engineered, mimic the immune system’s own antibody response to a specific antigen. What was the B-cell seminal discovery that revolutionized disease care in the 21st century?
A vast number of nonspecific biologics drugs treat a range of autoimmune (CI) diseases. Can you name the major categories of biologics and give examples in each category?
In appreciation for July 2023 updates to this Blog by Marjorie A. Shapiro, Ph.D.
Chief, Laboratory of Molecular and Developmental Immunology
Division of Biotechnology Review and Research
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