What are biologic drugs.

The term “biologic drugs " indicates all those new generation drugs produced to act only on a single structure, which can be a protein, a receptor, or even a DNA sequence, increasing the effectiveness of the therapy and reducing, at the same time, side effects.

These drugs are the result of knowledge achieved in the biotechnology field. They are synthesized through sophisticated recombinant DNA procedures. It would, therefore, be more appropriate to call them "biotechnological" drugs. They are produced from proteins present in our bodies, which are modified in the laboratory. Usually, it is a matter of "reprogramming" antibodies (but not only) in such a way as to make them active only on a specific target. To date, biologic drugs are available against autoimmune diseases, for example, lupus, rheumatoid arthritis, and psoriasis. 

Moreover, there are chronic inflammatory diseases of the intestine, such as Crohn's disease and ulcerative rectocolitis and some types of cancer (especially those of the breast, liver, kidney, and colon). 

Biologic drugs are complex protein molecules, produced in the laboratory within living systems (such as cells).

The synthesis of a biologic drug requires a very comprehensive production process. This process - the cells used, the procedures adopted - defines its characteristics; a modification in any part of the process can significantly alter the composition of the protein compound and, consequently, its effectiveness and any side effects.

What do biologic drugs do?

Biologic drugs are designed to act on a specific receptor, to modify the process of the disease itself. Monoclonal antibodies, gene therapies, and some types of hormones are biologic drugs. These compounds have provided new possibilities and methods for treating important diseases like cancer, diabetes, hepatitis, multiple sclerosis, and anemia. Monoclonal antibodies, used in cancer therapies, are designed to bind to cancer cells, recognizing specific proteins (receptors) on their surface. When the monoclonal antibody has bound to a cell, it sends the signal to the immune system to destroy it.

How do biologic drugs work?

Biologic drugs aim to reach diseased cells or structures, acting directly on them without damaging healthy cells. To achieve this goal, we decided to use the defenses of our body, namely, the antibodies, to modify them in such a way that they recognize sick structures (tumor cells) or proteins involved in the pathological process aggressors. As in the case of drugs designed to treat autoimmune diseases, such as rheumatoid arthritis, which are programmed to "attack" the pro-inflammatory cytokines released by the inflamed cells, to block inflammation.

Biologic drugs work in a similar way to that of proteins produced by our body. For example, our antibodies (which are proteins) recognize foreign proteins present in viruses and bacteria. They bind to them and block their activity, thus protecting us from infections.

Organic drugs:

The importance of the production process, unlike traditional drugs, obtained by chemical synthesis, biologic drugs requires particular attention regarding the production process. Their complex structure depends on the process. In other words, the production process determines the uniqueness and characteristics of the biologic drug. Precisely because of this complexity, the same molecule, if produced by different companies or even by the same company but with different production processes. It can present significant structural modifications and, therefore, different safety and efficacy characteristics. 

For these reasons, the national and international authorities delegated to authorize the marketing of drugs to monitor extremely carefully every process in the production and distribution chain of a biologic drug.

Due to their complexity, the production techniques of biologic drugs are particularly difficult to characterize and reproduce. This difficulty grows proportionally to the complexity of the molecule. For instance, a first-generation biologic drug, such as erythropoietin alfa - with a molecular weight of about 30,000 Daltons - is much simpler in size, weight, production characteristics, and mechanism of action compared to a monoclonal antibody, which weighs over 145,000 Daltons.

Which ones are they?

The biologic drugs most used so far in inflammatory diseases are TNF-α (Tumor Necrosis Factor alfa) inhibitors, a cytokine. It plays a central role in numerous chronic inflammatory diseases, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

The TNF-α inhibitors currently available belong to two different classes: monoclonal antibodies (infliximab and adalimumab) and soluble receptors (etanercept).

To these are added the drugs that antagonize the effects of interleukin 1 (anakinra), pro-inflammatory cytokine similar to TNF-α, the antagonists of interleukin 6 (tocilizumab). They act by reducing the circulating B lymphocytes (rituximab) or by reducing the activation of T lymphocytes (abatacept).

In the treatment of tumors, monoclonal antibodies are used, which are not always derived from human proteins and, therefore. Theoretically, not all of them fall into the category of "biologic" drugs. They are directed against objectives other than those illustrated above. In fact, they act on growth factors implicated in tumorigenesis. They essentially belong to three different classes:

Epidermal Growth Factor (HER-1) receptor one drugs

Cetuximab

Panitumumab

Erlotinib

Drugs against Vascular Endothelial Growth Factor (VEGF) and against Epidermal Growth Factor (HER-2) receptor 2 

Bevacizumab 

Trastuzumab

Multitarget drugs (act at different levels) 

Lapatinib

Sunitinib

Sorafenib

Indications

Biologic drugs have proven effective in several rheumatic diseases: rheumatoid arthritis (used in combination with antirheumatic background drugs), ankylosing spondylitis, and psoriatic arthritis, although the patients to whom they should be prescribed must be carefully selected.

The use of biologic drugs in the treatment of chronic inflammatory diseases other than those for which there is an authorized indication is, however, on the increase.

Numerous studies have been conducted in recent years to evaluate the efficacy of these drugs on tumors with very encouraging results.

It is possible that in the future, these agents will become a valid therapeutic option for other disorders, such as some forms of vasculitis.

Side effects

To date, thousands of patients have been treated with biologic drugs in which the safety of use has been demonstrated, at least in the short and medium-term.

The most frequent undesirable effect of biologic drugs that act on inflammation is the appearance of infections due to the reduction of immune responses induced by biologic drugs. In most cases, however, these are non-serious infections, although there is also a risk of severe infections, including tuberculosis's reactivation in patients with latent infection.

Reactions such as redness, itching, and swelling at the injection site of the drug or vasomotor crises during intravenous infusion are also reported. In some cases, the appearance of autoantibodies has been observed, which, only in a minority of patients, has been associated with typical manifestations of an autoimmune disease. As for the drugs used in tumors, the side effects are linked to the action on the different receptors. In particular, there are cutaneous effects for drugs that act on Epidermal Growth Factor receptors and cardiovascular effects for Vascular Endothelial Growth Factor inhibitors. Finally, it is also possible to explain the metabolic side effects that are difficult to explain based on the mechanism of action of the drugs in question.

The immunogenicity

Biologic drugs are proteins, and therefore the risk that they are recognized as foreign substances by the body must be considered, inducing an immune reaction that neutralizes their effectiveness. A fundamental characteristic relating to the efficacy and tolerability of biologic products is their immunogenicity, that is, the ability to induce an immune reaction in the organism. In fact, if the patient's organism recognizes a biologic drug as "foreign," it can neutralize its effect, preventing its therapeutic efficacy.

Immunogenicity, once induced, can lead to ineffectiveness of treatment, but in some cases even to more serious consequences (such as aplastic anemia for erythropoietin). The risk of immunogenicity of a biologic drug depends on several factors, including:

- The quality of the drug (impurities, the possible presence of contaminants deriving from the production process and capable of interfering with the activity of the drug)

- The characteristics of the production process

- The duration of the treatment

- The site of administration of the drug

- The characteristics of the individual patient (conditions of the immune system, genetic profile).

Author: Vicki Lezama