Cancer is one of the leading causes of mortality, accounting for 0.6 million deaths in 2022, in the US alone. Further, as per the International Agency for Research on Cancer (IARC), by 2040, there are likely to be 27.5 million new cases and 16.3 million deaths related to cancer annually. Although cancer therapeutics continue to be one of the most active areas, in terms of drug development, there is still a significant unmet need in this domain. Amongst various targeted therapies being evaluated for cancer, antibody drug conjugates (ADCs) have emerged as a highly potent option to selectively eliminate tumor cells with minimal side effects. These are an upcoming class of targeted therapeutic agents that have captured the attention of both large and small pharmaceutical companies, and academic / research institutions from all across the world. Fundamentally, these complex biotherapeutic entities demonstrate the combination of target specificity of an antibody and therapeutic features of a chemotherapy / cytotoxic drug. Such conjugates are believed to be more efficient and effective in specifically identifying and eliminating cells / pathogens that are associated with the disease(s). The global antibody drug conjugate market is anticipated to grow at a CAGR of around 9.63%, till 2035. Driven by the promising developmental pipeline, the antibody drug conjugate market is anticipated to witness a steady growth in the coming decade.
OVERVIEW OF ANTIBODY DRUG CONJUGATES
Antibody drug conjugates consist of an antibody and a small molecule drug. The molecule that links both the components is called a linker. Although both the molecules can be separately used as viable therapeutics, together, they become a guided therapeutic entity. It is worth highlighting that the mechanism of action of the conjugate is completely different from those of the individual components. The components are mentioned below:
- Antibody: The antibody is usually of monoclonal origin, which means that it identifies and binds to a specific receptor on target cells. These can be used to specifically target aberrant cells in cancer and other diseases. Thus, the main function of the antibody component in the antibody drug conjugate is to guide the conjugate to the target cells.
- Cytotoxin: The drug, also referred to as a cytotoxin, may be an antibiotic or any other agent that either has the capability to treat or cause the death of a diseased / transformed cell. Research has estimated that less than 0.1% of the injected antibody drug conjugates is taken up by the target cells. This requires the cytotoxin to be highly potent to ensure optimal therapeutic effects.
- Linker: The antibody and the cytotoxin are conjugated using a synthetic chemical linker, which ensures the integrity of the conjugate during circulation. The stability of the linker affects the efficacy and potency of the overall antibody drug conjugate molecule. It is essential that the linker remains stable in the bloodstream and is cleaved to release the drug, only when the conjugate is inside the cell.
ADVANTAGES OF ANTIBODY DRUG CONJUGATES OVER TRADITIONAL THERAPEUTICS
Antibody drug conjugates, or immune conjugates, combine the benefits of the individual components, and help eliminate some of the drawbacks inherent to each singular entity, when used as a therapeutic separately. Naked monoclonal antibodies are generally not effective enough to kill target cells every time (either by the stimulation of ADCC, or by blocking growth receptors present on the surface of cancer cells or blocking tumor promoting signals from cancer cells). Although individual antibodies can specifically bind to their cellular target, their ability to ensure cell death / clinical benefit is not guaranteed. As indicated earlier, treatment options that use cytotoxins / drugs are prone to cause adverse side effects owing to the non-specific nature of these small molecules. This causes the loss of healthy cells in the body.
Therefore, within an antibody drug conjugate, the two components complement each other. Once the complex is administered in vitro, specificity is provided by the monoclonal antibody, while the drug provides the required clinical effect. Additionally, the controllable warhead activation and release mechanism of an antibody drug conjugate makes it more target specific compared to the small molecules, which further ensure increased patient compliance. antibody drug conjugates also take longer duration of time to develop resistances against the mutations contributing to its wider therapeutic window. In order to obtain highly selectable antibody drug conjugates with enhanced efficacy linkers, sites for monoclonal antibody attachment and cytotoxic payloads are thoroughly optimized. The selection of linkers is based upon various parameters, such as heterogeneity, specificity of expression, copy number, internalization rate and intracellular trafficking. Recent optimization for antibody drug conjugates includes the addition of cytotoxic drugs that are hundred to thousand folds more potent than the earlier used types. Examples of such drugs are calicheamicin and maytansinoids.
PHARMACOKINETIC PROPERTIES OF ANTIBODY DRUG CONJUGATES
The pharmacokinetic properties of antibody drug conjugates regulate their half-life, concentration and other key properties. The optimization of these properties is vital for the antibody drug conjugates interaction with the molecular target, its internalization and the subsequent release of the drug inside the cell. The various pharmacokinetics properties of antibody drug conjugates include:
- Absorption: The currently available antibody drug conjugates in the market are delivered intravenously, as a result of which, absorption has not been a well-studied parameter while assessing the pharmacokinetic property of the antibody drug conjugate. However, other routes of administration, such as subcutaneous, are often used in preclinical studies to establish drug safety. Although the mechanism of absorption is not well-established, the primary pathway for the absorption of antibody drug conjugates has been postulated to be the lymphatic drainage pathway, which allows absorption from the site of subcutaneous administration to systemic circulation. Moreover, molecular diffusion across the blood vessels is often considered to regulate the drug absorption kinetics.
- Distribution: In general antibody drug conjugates demonstrate distribution characteristics similar to that of monoclonal antibodies. However, the cytotoxic payload, as well as the attached monoclonal antibody affects the distribution of the molecular complex. Specific to the cytotoxic payload, the internalization, and the rate at which the payload is internalized, affects the accumulation of the drug inside the tumor / diseased cell. To maintain optimal distribution, the payloads are linked with molecules, which are designed to be stable in circulation. Once inside the cell payload linked to the molecule undergoes sufficient cleavage by endosome / lysosome. Moreover, the endocytic recycling of the target on the cell surface plays a key role in maintaining sustained delivery of the payload inside the tumor cell. Meanwhile, the shedding of the target from the cell surface can modify the distribution profile and influence a drug’s efficacy and toxicity.
- Metabolism and Elimination: Metabolism of antibody drug conjugates generally involves the following three processes:
- De-conjugation by enzymatic or chemical processes to release the cytotoxic payload
- Proteolytic metabolism of the conjugated antibody producing peptides and amino acids that are often attached to the cytotoxic payload
- Phase I and phase II metabolic enzymes induced metabolism of the cytotoxic payload
The de-conjugation of antibody drug conjugates is primarily driven by the type of linker attached to the payload. The linkers are either cleaved by specific proteases or by proteolytic processing in the endosomes / lysosomes. Following cleavage, the payload is released. The release of the payload is dependent on properties of the target, stability of the linker and the drug to antibody ratio of the antibody drug conjugate. The released drug is then metabolized by processes, which are similar to that involved in the degradation of small molecule drugs. The alteration of antibody drug conjugate heterogeneity has also been demonstrated to play a role in antibody drug conjugate metabolism and elimination.
CONCLUDING REMARKS
Over the years, several developments have been reported in this field and antibody drug conjugates have been successful in carving out a significant niche in the pharmaceutical market. A number of such therapies have already been approved, and a robust development pipeline indicates that the antibody drug conjugates market will continue to grow in the foreseen future. Moreover, the ongoing research activity in this field has led to the discovery of several novel molecular targets, further strengthening the research pipelines of companies engaged in this market. Currently, several industry and non-industry players are focused on the development of technologies that are capable of overcoming the existing roadblocks in the production / adoption of antibody drug conjugates. Driven by the availability of innovative technology platforms, lucrative funding opportunities and encouraging clinical trial results, the antibody drug conjugates market is poised to grow in the long-run, as multiple product candidates are expected to receive marketing approval in the coming decade.
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