THE NEXT GENERATION ANTIBODIES: DUAL EFFECT OF BISPECIFIC ANTIBODIES (bsAbs)

Updated: Mar 1


Antibodies (Abs) are essential for the body's immune system to function properly. These are produced by a specialized group of white blood cells called B lymphocytes, and their primary function is to combat the harmful effects posed by the entry of foreign species like germs or viruses into the body thus preventing it from getting sick. The antibody's usual structure comprises four chains- two heavy and two light chains that are linked covalently by disulphide bonds. The antibody is divided into two antigen-binding fragments (Fab) and an “inactive” crystallizable fragment (Fc) forming the trunk of the distorted Y shape susceptible to hydrolysis. These arms are highly specific to their respective targets. Recent advancements and the development of innovative and inventive techniques have allowed us to harness the true credibility of novel antibodies.

Monoclonal Abs (mAbs) are engineered in the laboratory from a single clone of immune cells which means that every mAbs produced by the immune cell is exactly the same. mAbs have materialized as a crucial and efficient option in immunotherapy. However, several mediators contribute to trigger distinct signaling pathways or facilitating overlapping signaling cascades in the complex pathophysiology of a disease. These factors limit the therapeutic benefit of targeting a single molecule. To counter these limitations, the concept of bispecific antibodies was then introduced in the pharmaceutical field because they permit unconventional and often therapeutically supreme mechanisms of action, which are not accessible to monoclonal antibodies.

Bispecific antibodies (bsAbs) are biotherapeutics that attach to two separate targets or epitopes on a single target. bsAbs-based immunotherapy due to its synergistic effect is gaining momentum in the treatment of complex diseases such as viral infections, autoimmune diseases, and cancer, attributed to the presence of multiple targets. Each of the bsAbs are thus designed in such a way that they execute a distinct function in a specific disease.

Bispecifics have a two-arm structure, and this facilitates the placement of a therapeutic agent on one arm and simultaneously allowing the other one to target the diseased site specifically. A toxin, drug, DNA, or an enzyme can be used as a therapeutic agent. Researchers have identified the unique applications of this double specificity. For example, while treating cancer, one arm of the bispecific redirects the cytotoxicity of immune effector cells called the T cells towards the protein overexpressed on the cancerous B cell. This induces a systemic response by the body’s immune system to detect and attack the cancerous cells. Another important application is to block two different proteins that both contribute to disease. Bispecifics can also act as bridges in building protein complexes or activate cell signaling pathways by bringing ligands and receptors together.

Due to the stability and predictability of antibodies, it can be hard to force two features in one molecule. With decades of research and experimentation in understanding the structure of a number of natural and engineered antigen-binding immunoglobulin domains along with an improved knowledge of molecular mechanisms of numerous biological activities, some positive results are evident in recent studies. In 2009, the first bispecific antibody, catumaxomab, was licensed for cancer treatment, along with two BiTE molecules (MT103 and MT110), which showed promising outcomes in early clinical trials. The first bispecific antibody named catumaxomab was approved for cancer therapy in 2009 along with two BiTE molecules (MT103, MT110) which have reported some favourable results in the first clinical studies. Although catumaxomab was taken off the market in 2017 for commercial reasons, blinatumomab (CD3B lymphocyte antigen CD19), a T cell-engaging bsAb (bsTCE), showed promising results in clinical studies, reigniting interest in the idea. Although catumaxomab was withdrawn from the market in 2017 citing commercial reasons, T cell-engaging bsAb (bsTCE), blinatumomab (CD3×B lymphocyte antigen CD19) showed impressive results in the clinical trials and thus renewed interest in the concept.

To mimic and enhance the targeting precision of the natural antibodies, bispecifics are produced based on genetic engineering, transgenic mouse technologies, and hybridomas which has given rise to a range of recombinant bispecific antibody formats over the past two decades. This has further contributed in revolutionizing the development of versatile bispecifics in therapeutic and diagnostic fields by giving the scientific community an opportunity to modify the valency, size, flexibility, and biodistribution of bsAbs to appropriately fit the desired target-product profile.


 

Edited and approved by- Dr. Jyoti Chhibber-Goel and Dr. Bharti Singal

#bispecifics #antibodies #cancertherapy #targetedtherapies #pharmaceutical

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