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Written by: Hanna Fleisher

Dear friends, we continue investigating the area of scientific history of patents and pharmaceuticals. Let us remind you that when conducting patent research (e.g., various searches, expert opinions, patent strategies, etc.), we study the development of certain pharmaceutical areas and active substances. It is not for everyone :). But those who are familiar with the matter and curious about development of science in the pharmaceutical direction may be interested. Therefore, we invite you to read our new article.

Today’s article addresses Immunoglobulins.

A living organism is able to “read” the structure of an antigen and subsequently synthesize antibodies complementary to it

Immunoglobulins (antibodies) are large globular blood plasma proteins secreted by cells of the immune system and designed to neutralize pathogens (bacteria, fungi, multicellular parasites) and viruses, as well as protein poisons and some other extraneous substances. Each immunoglobulin recognizes a unique element of the pathogen, which is absent in the body itself – an antigen. By binding to antigens on the surface of pathogens, immunoglobulins can directly neutralize them, or recruit other components of the immune system, such as the complement system and phagocytes, to destroy extraneous cells or viral particles.

Structurally, immunoglobulins are Y-shaped and consist of two identical light and two identical heavy polypeptide chains joined together by disulfide bonds. The two “upper” ends of polypeptide chains end with amino groups and two identical antigen binding sites are located on them, and the third end terminates with a carboxyl group and is one of several types. Heavy (H) and light (L) chains exist in several variants, differing in structure and function, in connection with which immunoglobulins are divided into classes, or isotypes. There are two types of L chains (κ and λ) and five isotypes of H chains (μ, γ, α, δ and ε). There are five main types of antibodies in mammals: IgM, IgG, IgA, IgD and IgE. Immunoglobulins of all classes have the same light chains – κ and λ, but the structure of their heavy chains is different.

Medicines based on immunoglobulins (or antibodies) have been known for a long time. At the end of the 19th century, the German scientist Emil Behring invented a drug for the treatment of diphtheria based on the blood serum of patients. The very first dose of the immunoglobulin medicine was administered on Christmas night 1891 at the Bergmann Children’s Hospital in Berlin, and the inventor later received the Nobel Prize in Physiology and Medicine for “a victorious weapon against disease and death.” The second Nobel Prize went to Paul Ehrlich in 1908 for the discovery of antibodies and the justification of the humoral theory of immunity.

The practical use of immunoglobulins became possible only in the 1950s after Edwin Kohn (1952) had developed the method of alcohol fractionation of blood plasma. It is interesting that the term “immunoglobulin” itself was invented later than the method of its isolation – in 1959, and the next Nobel Prize for deciphering the chemical structure of immunoglobulins went to Gerald Edelman and Rodney Porter in 1972.

Early research and use of immunoglobulins focused primarily on class G (IgG) and class M (IgM) immunoglobulins. New immunoglobulin isotypes were identified in the 1960s. Thomas Tomashi described the secreted immunoglobulins IgA, David Rowe and John Fay discovered IgD, and Kimishizi Ishizaka and Teruko Ishizaka discovered IgE. In 1976, Suzumi Tonegawa began a series of experiments and showed that genes encoding immunoglobulins undergo rearrangements, due to which a huge variety of immunoglobulins is created. It is worth noting that the drugs of the first generation, obtained from blood plasma, were polyclonal and heterogeneous, therefore, they contained a large variety of immunoglobulins, each of which differed in its specificity, and were administered intramuscularly. Such immunoglobulins had pronounced side effects, and the dosage form itself caused painful sensations and limited the volume permissible to be administered into the body. However, in the 1970s and 1980s, new technologies made it possible to create immunoglobulins for intravenous administration (IVIG).

One of the turning points in the development of the immunological field is creating the cell hybrids – hybrids capable of synthesizing immunoglobulins that specifically interact with a given antigen. These immunoglobulins were called monoclonal antibodies, and the inventors of the first hybridoma, Georges Köhler and Cesar Milstein, got the Nobel Prize in 1984. Since then, blood plasma ceased to be the only source of immunoglobulins.

The technology for hybridoma preparation was not patented, so hybridization spread freely and quickly to many laboratories around the world, accelerating the development of the immunological field

By the way, the lack of a patent for the method of hybrid preparation is not a conscious altruistic decision, but a big mistake. In July 1975, one of the specialists of the Medical Research Council (MRC) noticed Cesar Milstein’s technology, which was extremely attractive for commercialization, and asked the latter to send him an unpublished version of an article describing the method, which at that time was already awaiting a review in Nature. It should be noted that the Medical Research Council (MRC) itself did not have the right to patent inventions. Instead, the National Research Development Corporation (NRDC) was involved. An MRC representative immediately forwarded an application to NRDC to inquire about the possibility of the patenting, but did not receive any response. Milstein and Koehler’s paper appeared in Nature in August 1975, and it was not until October 1976 that the NRDC issued a reply to the MRC stating that the hybridoma method could not be patented because it had previously been published in a scientific journal. This precedent caused great anger among political figures, in particular Margaret Thatcher, while Cesar Milstein, on the contrary, believed that the absence of the patent was a blessing that helped him freely share his scientific results.

Getting back to the point, the monoclonal antibodies were originally mouse, and not human. Thus, in 1985, the Food and Drug Administration (USA) approved the first drug based on a mouse monoclonal antibody. However, such drugs naturally caused an immune reaction to the extraneous protein in humans. Therefore, in 1988, a method of humanizing monoclonal immunoglobulins was developed, which allows removing mouse protein extraneous to humans from immunoglobulin as full as possible. This is how chimeric and humanized antibodies appeared. If in chimeric antibodies the areas that directly recognize the antigen are of mouse origin, and the rest, bigger portion of the antibody, is of human origin, then in humanized antibodies the portion of the mouse material is even smaller.

The development of the immunological field does not end at the stage of monoclonal antibodies, but proceeds mainly along the preparation of modified monoclonal antibodies and their fragments, as well as the use of a dosage form for intravenous administration. However, despite all the achievements, the current market of immunoglobulin medications is represented by both products obtained by genetic engineering and obtained from blood plasma. Today, there are four types of drugs:

– standard immunoglobulins for intravenous administration – standard immunoglobulins of the IgG class, that have a single international non-patented name – normal human immunoglobulin for intravenous administration; the main indications are prevention or immunotherapy, as well as therapy of autoimmune diseases;

Medicinal products based on normal human immunoglobulin are not generics, because they differ in production method, composition, content of IgA and IgM, composition of IgG subclasses, methods and number of stages of inactivation and elimination of viruses

– enriched immunoglobulins for intravenous administration – IVIG, that contain immunoglobulins of the IgG class and are enriched with immunoglobulins of the IgM and IgA classes; the main indication is adjuvant therapy of bacterial infections;

– specific or hyperimmune immunoglobulins for intravenous administration – IVIG, that contain immunoglobulins of the IgG class, while their concentration against certain pathogens is much higher than that of standard immunoglobulins, for example, anticytomegalovirus IVIG and immunoglobulin enriched with antibodies to HBs; indications include the treatment of active cytomegalovirus infection in immunocompromised patients, pregnant women, newborns and young children / prevention of hepatitis B infection;

– combined medications that contain immunoglobulins and other active pharmaceutical ingredients (for example, a combination of immunoglobulin and interferon).

What favorably distinguishes immunoglobulins from all the variety of state-of-the-art medicines is the ability to quickly (but not cheaply) prepare specific immunoglobulins for any microorganism and use them for the treatment of seriously ill, and sometimes hopelessly ill patients.

Thanks to everyone who read and was interested.

Best regards,

Team of Intectica group.

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