Proteins As Drugs

Therapeutic Proteins

Protein-based therapeutics has made an incredible progress over the past 20 years.

Protein therapeutics can be grouped based on their molecular types that include antibody-based drugs, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, Fc fusion proteins, growth factors, hormones, interferons, interleukins, thrombolytics and peptides.

Most protein therapeutics currently on the market are recombinant and hundreds of them are in clinical trials for therapy of cancers, immune disorders, infections, and other diseases. Newly engineered proteins, including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small molecule drugs, and proteins with optimized pharmacokinetics, are currently under development.

Examples of Therapeutic Proteins

Antibodies

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mostly by differentiated B cells called plasma cells, that is used by the immune system to fight off pathogens such as bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen, via the fragment antigen-binding (Fab) variable region. 


1. Fab region

2. Fc region

3. Heavy chain (blue) with one variable (VH) domain followed by a  constant domain (CH1), a hinge region, and two more constant (CH2 and CH3) domains 

4. Light chain (green) with one variable (VL) and one constant (CL)
domain

5. Antigen binding site (paratope)

6. Hinge regions 

 

Most of current therapies use monoclonal antibodies. Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient’s immune system to attack those cells. Alternatively, in radioimmunotherapy a lethal radioactive dose is delivered to a targeted cell line. More recently antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy. It is possible to create a mAb that is specific to almost any extracellular/cell surface target. Research and development is underway to create antibodies for diseases, such as rheumatoid arthritis, multiple sclerosis, Alzheimer’s disease, Ebola and different types of cancers.


Conjugates of small molecule drugs with antibodies (ADCs) and with other proteins (protein-drug conjugates, PDCs) are used as a new class of therapeutics combining the specificity of monoclonal antibodies (mAbs) and other proteins with potent cytotoxic activity of small molecule drugs for the treatment of cancer and other diseases. A(P)DCs have three major components, antibody (targeting protein), linker and payload, the cytotoxic drug. Examples of antibody drug conjugates structures: 

 

 

Hormones

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mostly by differentiated B cells called plasma cells, that is used by the immune system to fight off pathogens such as bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen, via the fragment antigen-binding (Fab) variable region. 

Enzymes

Enzymes are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules
upon which enzymes may act are called substrates, and the enzyme
converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. 

 Enzymes as therapeutics hold a few advantages over non-enzymatic drugs with their amazing specificity towards targets, as well as multiple substrates conversion. Enzymes can be used to treat important, rare, and deadly diseases. Enzyme therapy is the only available treatment for certain disorders. Enzymes are categorized in four main groups, enzymes in replacement therapy, enzymes in cancer treatment, enzymes for fibrinolysis, and enzymes that are used topically for various treatments. 

Bone Morphogenic Proteins

Enzymes are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules
upon which enzymes may act are called substrates, and the enzyme
converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. 

 Enzymes as therapeutics hold a few advantages over non-enzymatic drugs with their amazing specificity towards targets, as well as multiple substrates conversion. Enzymes can be used to treat important, rare, and deadly diseases. Enzyme therapy is the only available treatment for certain disorders. Enzymes are categorized in four main groups, enzymes in replacement therapy, enzymes in cancer treatment, enzymes for fibrinolysis, and enzymes that are used topically for various treatments. 

Interferons

Interferon is a protein released by human and animal cells, usually in response to the entry of a virus, which has the property of inhibiting virus replication.

Interferons (IFNs) are attractive biological response modifiers for use as therapeutic agents in infectious diseases, because they have both antiviral and immunomodulatory activities. Their name even comes from the fact that they can “interfere” with viral replication. IFN-α (“leukocyte interferon”) and IFN-β (“fibroblast interferon”) are released by human cells infected with certain viruses, whereas IFN-γ (“immune interferon”) is produced by natural killer (NK) cells (T-cell lymphocytes) in response to antigen exposure. These cytokines then act on uninfected host tissue cells to induce a state of relative resistance to viral infections. List of commercially available interferon products:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134994/table/tbl1/?report=objectonly

Anticoagulants and Blood Factors

Interferon is a protein released by human and animal cells, usually in response to the entry of a virus, which has the property of inhibiting virus replication.

Interferons (IFNs) are attractive biological response modifiers for use as therapeutic agents in infectious diseases, because they have both antiviral and immunomodulatory activities. Their name even comes from the fact that they can “interfere” with viral replication. IFN-α (“leukocyte interferon”) and IFN-β (“fibroblast interferon”) are released by human cells infected with certain viruses, whereas IFN-γ (“immune interferon”) is produced by natural killer (NK) cells (T-cell lymphocytes) in response to antigen exposure. These cytokines then act on uninfected host tissue cells to induce a state of relative resistance to viral infections. List of commercially available interferon products:

Fusion Proteins

A fusion protein is a protein consisting of at least two
domains that are encoded by separate genes, that have been joined so that they are transcribed and translated as a single unit, producing a single polypeptide. Fusion proteins can be created in
vivo, for example, as the result of a chromosomal rearrangement. The Bcl–abl fusion protein, which causes chronic myelogenous leukemia, is an example of such a fusion protein. Fusion proteins can also be created in vitro using recombinant DNA techniques. 


Chimeric fusion proteins, with their ability to extend plasma half-life and prolong therapeutic activity, offer exciting benefits over antibody-based therapeutics. Companies are intensely investigating into fusion protein therapeutics as a promising alternative to antibodies.  Since Enbrel, the first fusion protein drug was approved by the FDA in 1998, other fusion protein therapeutics were approved as well, such as: VEGFR Fc-fusion (Eylea), CTLA-4 Fc-fusion (Nulojix), Glucagon-like peptide – 1 receptor agonist Fc-fusion (Trulicity), VEGFR Fc-fusion (Zaltrap), Recombinant factor IX Fc fusion (Alprolix), Recombinant factor VIII Fc-fusion (Eloctate), Albumin fusion. 

Peptides

Peptides are short chains biomolecules consisting of two to fifty amino acids, linked by peptide bonds. Chains of fewer than ten or fifteen amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A polypeptide is a longer, continuous, unbranched peptide chain of up to approximately fifty amino acids. Chains are longer than 50 amino acids are known already as proteins.

Peptides are of particular interest as therapeutic drugs, because the human body naturally produces many different peptides, this means they are relatively well-tolerated as therapeutics and have fewer side-effects.

There are over 60 peptide based therapeutics currently available on the market

https://www.researchgate.net/figure/List-of-marketed-peptide-drugs_tbl1_264091042