The pharmaceutical industry is always on the lookout for innovative treatment options. The discovery of the therapeutic potential of monoclonal antibodies and its successful implementation in the treatment of several diseases and biological disorders has revolutionized the pharmaceutical industry. Presently, there are several research efforts being made into engineering antibody therapeutics in order to further improve treatment-related outcomes. A few decades ago, bispecific antibodies were first developed by the incorporation of additional antigen binding sites into monoclonal antibodies. The primary objective of such bivalent molecules has, so far, been to redirect cytotoxic immune effector cells for augmenting the killing of tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and other cytotoxic mechanisms mediated by the immune effector cells. This modified form of antibody-based therapeutics is currently gaining a lot of attention from both large and small pharmaceutical companies. The global biospecific antibodies market is anticipated to grow at a CAGR of around 9.5%, till 2035, according to Roots Analysis. In the foreseen future, as more therapeutic candidates move into the clinical stage and / or receive approval, we anticipate the bispecific antibody therapeutics market to witness healthy growth.
Theoretically, these advanced biologic molecules have the capability to overcome the setbacks of monoclonal antibodies and also offer improved drug efficacy at lower doses. Bispecific antibodies are generated either by making alterations to different domains of an antibody, or by joining two different antibodies for enhancing their effector functions and efficacy. The primary effector functions include ADCC, complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP) and increasing the half-life of the molecule. These properties of the molecule augment the clinical performance of the antibody as a therapeutic.
Bispecific antibodies refer to bioengineered antibodies that comprise of two different binding sites within a single molecule. A bispecific antibody is a second-generation immunotherapy and is essentially an upgraded version of a monoclonal antibody, with improved structure and functionality. These are basically conjugated artificial antibodies that are formed by the physical fusion of two monoclonal antibodies, or the specificity determining regions of two monoclonal antibodies; this results in the formation of an antibody candidate that has two different binding arms to bind to two (or three) different epitopes, simultaneously. These combinations have been demonstrated to display additive, and sometimes even synergistic effects, in combating disease. This is because several signaling pathways are involved in the pathogenesis of most diseases, and a therapeutic agent that can affect multiple pathways simultaneously, is likely to be more efficient in treating the condition. Additionally, various technologies have been developed to discover and generate bispecific antibodies. Some of these technologies include the Quadroma technology, knobs-into-holes (KiH) technology and CrossMAb technology. Additionally, the utilization of peptide linkers and recombinant DNA technology have been widely employed for the development of these molecules.
Depending on the structure of a bispecific antibody, and its affinity towards its targets, it is likely to have different mechanisms of action. These mechanisms are highlighted below:
- Targeted Cell Killing: Bispecific antibodies can bind to a cancer cell and an immune cell (like T cells or natural killer cells). This brings the immune cell in close proximity to the cancer cell, facilitating its destruction.
- Redirected Cytotoxicity: They can redirect immune cells to attack a specific target, such as cancer cells. By binding to both the target and immune cells, they enhance the specificity of the immune response.
- Dual Targeting: Some bispecific antibodies target two different molecules involved in a disease process, disrupting signaling pathways or neutralizing multiple disease-related targets simultaneously.
- Drug Delivery: Bispecific antibodies can carry a payload, like a toxin or drug, to a specific target. They bind to the target on one end and release the payload to exert a therapeutic effect.
- Blocking Signaling Pathways: In certain diseases, they can bind to a receptor on one end and a signaling molecule on the other, disrupting harmful signaling pathways.
- Tumor Microenvironment Modulation: Bispecific antibodies can also be designed to target components of the tumor microenvironment, such as stromal cells or angiogenic factors, to modulate the tumor environment and hinder its growth.
As demonstrated earlier, several types of bispecific antibodies with varying specificities and modes of action have been developed in recent years. Bispecific antibodies have evolved into indispensable entities that are required for a plethora of applications in various fields, such as medicine and biomedical research. Some of the applications of these antibodies are discussed below:
- Bispecific Antibody as a Therapeutic Modality: As mentioned earlier, bispecific antibodies are being investigated for the treatment of cancers, autoimmune diseases, infectious diseases and blood disorders. Bispecific antibodies are being investigated for various advanced and complex therapeutic purposes.
- Bispecific Antibodies in Crossing the Blood Brain Barrier (BBB): This is one of the most promising therapeutic applications of bispecific antibodies. At present, there are no monoclonal antibodies that possess the ability to cross the BBB. The ability to cross this barrier would open up a number of opportunities for targeting pathogenesis mediators of neurological diseases. The binding between bispecific antibody and TfR enables the therapeutic entity to cross the BBB crossing via receptor mediated transcytosis. The affinity between the bispecific antibody and TfR is weak that allows them to be released from the endothelium and cross the BBB to target the disease mediator, BRACE1 (using its other binding arm).
- Bispecific Antibodies Targeting Antibiotic Resistant Pathogens: Owing to the overuse of broad-spectrum antibiotics, many pathogenic strains of microorganisms have become resistant to antibiotic therapies. Some microbial strains are found to be resistant to even more than one antibiotic, which makes the treatment of diseases caused by such pathogens even more difficult. Therefore, in order to overcome this problem, a number of companies are working to develop bispecific antibodies that have the capability to target these molecules.
- Bispecific Antibody in diagnostics / immunoassays: Bispecific antibodies can also be used as diagnostic tools. They can be specifically designed to target specific antigens for the detection of certain substances. These molecules can act as cross-linkers, which bind to antigens and reporter molecules, such as horseradish peroxidase, simultaneously. Bispecific antibody based diagnostic assays can be performed for detecting infections such as tuberculosis, hepatitis B, E.coli infections, whooping cough (Bordetella pertussis), severe acute respiratory syndrome (SARS) and other infections. Additionally, these molecules can be used in immunohistochemistry and radio immune diagnosis applications as well.
- Bispecific Antibodies as Delivery Vehicles: This is the one of the most interesting applications of bispecific antibodies; bispecific antibodies can be used for the delivery of various types of payload entities, such as drugs, nanoparticles and radiolabels. Researchers have already tested the applicability of such molecules in a preclinical study. TF2 is a bispecific antibody that targets CEA and 99mT-labeled hapten histamine-succinyl-glycine (HSG). The antibody was developed using the DNL method and can be used for tumor imaging or radioimmunotherapy applications. During the preclinical study, the bispecific antibody was initially injected and 99mT-labeled hapten HSG was then administered post the clearance from bloodstream. The results demonstrated the successful use of the bispecific molecule in the administration of 99mT-labeled HSG for tumor imaging.
The future of biospecific antibodies holds great promise in revolutionizing the field of medicine and therapy. These engineered molecules, with their ability to precisely target multiple molecules or cells simultaneously, are poised to play a pivotal role in personalized medicine. One of the most exciting prospects is their application in cancer therapy, where they can enhance the specificity and effectiveness of immune responses against tumors, potentially leading to more durable and less toxic treatments. Additionally, biospecific antibodies could revolutionize the treatment of autoimmune diseases by selectively modulating immune responses. Beyond oncology and immunology, they offer new avenues for tackling infectious diseases, neurological disorders, and a wide range of other conditions. As research and development in this field continue to advance, we can anticipate the emergence of innovative therapeutic strategies and a broader array of treatment options, ultimately improving patient outcomes and quality of life.
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