Innovative Medicines

In chemically synthesized medicines, the active ingredient is a chemical compound, also known as a small molecule. They are considerably smaller in size than biological molecules, such as proteins, and are administered orally ( tablet, capsule, or solution), although in some cases they may also be administered by injection or infusion.

Due to their size, chemical compounds can pass through the cell wall and attach to their receptors inside the cell. They are also designed to cross the blood-brain barrier and bind to target receptors associated with neurological diseases.

A protein is a large molecule made up of a long chain of amino acids and folded in a certain three-dimensional way. The specific sequence of amino acids and the 3D shape determine its biological function.

Technically, any drug based on a protein is a 'therapeutic protein'. This term was first used to describe drugs developed from genetically engineered versions of naturally occurring human proteins.

Therapeutic proteins can be used to replace an altered or deficient protein in a specific disease. They can also be used to ensure the supply of a beneficial protein to the body, in order to lessen the impact of disease or chemotherapy.

Genetically engineered proteins can be very similar to the natural proteins they replace, or they can be optimized by adding sugars or other molecules that prolong the duration of activity of the protein.

Monoclonal antibodies are bioengineered molecules designed to target specific protein targets involved in disease. Drugs composed of this class of molecules can be directed against receptors located outside cells or on the cell surface, since due to their size they cannot always reach receptors inside cells. They also tend to stay in the body longer than other drugs, so they are given less frequently.

As with natural antibodies, monoclonals also possess an immune-stimulating domain (the Fc region), which helps mount a more extensive immune response to the threats detected by the antibodies.

Natural antibodies act as one of the main gatekeepers of the immune system. These large, Y-shaped molecules contain two variable domains (the Fab regions), designed to recognize and bind to specific antigens considered a threat to the human body. The antigen against which they are directed may be a protein from a pathogen or a protein marker present in malignant or infected cells.

Fusion proteins are the result of the design of molecules that contain genes or gene fragments that encode the proteins.

For example, several fusion proteins have been developed by combining the binding domain of a cell surface receptor with the tail (Fc) portion of an antibody. The receptor portion acts as a decoy binding site that attracts and entraps molecules that, when free, contribute to disease development. The antibody portion allows the fusion protein to remain in the body much longer than a circulating receptor itself could.

Conventional antibody drugs are designed to specifically target a single antigen. However, many complex diseases are caused by numerous factors, so inhibition of a single antigen would not achieve sufficient efficacy. For example, in some diseases, cells respond to inhibition of one receptor by producing more of a second receptor, thus avoiding the effect of the drug.

Bispecific antibodies attempt to treat complex and multifaceted diseases. While natural antibodies have two arms to bind to the same target antigen, bispecifics are engineered hybrid molecules that have two different binding domains directed against two different antigens.

The term peptide is applied to small proteins made up of short chains of amino acids (about 40 or less). The body uses a wide variety of peptides, which act like hormones, and signaling molecules, which stimulate and regulate the main biological pathways. Some well known examples of natural peptides are insulin, endorphins and somatotropin (growth hormone).

Peptide drugs can be used to replace or mimic the functions of natural peptides or to emulate the ability of peptides to bind to their receptors in a potent and selective manner. Some peptide treatments are developed using chemical processes, while others are produced using genetically modified cells.

Despite the fact that peptides have functions and attributes that give them important therapeutic properties, they are quickly eliminated from the body. Therefore, peptide drugs must be administered by daily injections, limiting their use to a relatively small group of diseases.

By fusing a peptide with an antibody or a portion of an antibody, a peptibody is obtained that combines the activity of a peptide with the longer lasting activity of an antibody.

Many drugs used to treat cancer have toxicities that cause serious side effects, limit the dose and efficacy of these drugs, and place a large burden on patients. One possible way to reduce these problems is through the use of an antibody-drug conjugate (CAF).

CAF is engineered by linking cytotoxic cancer drug molecules with antibodies or antibody fragments. The portion of the CAF formed by an antibody can be designed to target specific proteins, primarily present on tumor cells.

The purpose of this process is to direct the cytotoxic fraction more directly to tumor cells and reduce collateral damage to healthy tissue. Both parts of the CAF (the targeting and cytotoxic portion) can be modified to target a wide variety of tumors with different antineoplastic drugs.

Most drugs work by binding to proteins involved in the disease and altering their activity. RNA interference (RNAi) is a technology that works by preventing cells from making a specific protein that contributes to disease development. This technology, also known as gene silencing, is based on the natural processes cells use to regulate protein expression.

The most common form of RNAi uses small RNA interference (siRNA) molecules. Those double-stranded RNA molecules are typically 21 nucleotides long. Once inside the cell, the siRNA fragments are processed by a mechanism consisting of numerous proteins and pairs with a complementary strand of messenger RNA. The messenger RNA is then degraded, preventing the production of the protein it encodes. Therapeutic siRNAs contain a highly specific sequence of messenger RNA for their target protein. siRNA is capable of silencing proteins that are difficult to address by other modalities.

Cytotoxic T cells play an important role in the body's immune defense by identifying and eliminating cancer cells; however, cancer cells can develop mechanisms to evade

T-cell recognition and destruction.

Bispecific T-cell Engager (BiTE^®) technology is designed to overcome cancer cells’ evasion of the immune system by engaging patients' own T cells to directly target cancer cells. BiTE^® molecules are comprised of two flexibly linked, single-chain variable fragments, with one designed to bind specifically to a selected cell surface tumor-associated antigen and the other to bind CD3, a component of the T cell receptor found on the surface of T cells.

Amgen has also advanced half-life extended BiTE^® molecules that contain a silenced fragment crystallizable (F) domain. The Fc domain is designed to increase the amount of time that the half-life extended BiTE^® molecule is in circulation and allow for less frequent administration.

BiTE^® technology aims to provide a targeted immunotherapy approach in both hematologic malignancies and solid tumors.