Introduction
Antibody-drug conjugates (ADCs) are a type of biologic drug that can bind to specific targets and modulate immune responses. They are used to treat various diseases, such as cancer, autoimmune disorders, and infectious diseases. The development of ADCs is not a simple task, as it involves many challenges and complexities in three main aspects: linker technology, drug payloads, and manufacturing. ADCs are a rapidly evolving and promising modality that offers new therapeutic opportunities and challenges for the biopharmaceutical industry.
They combine the specificity of antibodies with the potency of cytotoxic drugs. ADCs have shown exciting potential in the treatment of various cancers, especially those that are resistant to conventional therapies. They can enhance the efficacy and safety of existing therapies, such as chemotherapy, radiotherapy, and immunotherapy, by increasing the specificity and reducing the side effects of the treatment. ADCs can target novel antigens and mechanisms of action, such as DNA damage response, apoptosis, and immune modulation, which can overcome resistance and relapse of cancer cells. Finally, there are new modalities and formats, such as bispecific ADCs, ADCs with dual payloads, and ADCs with site-specific conjugation, which can improve the stability, potency, and homogeneity of the ADCs.
In this review article, we will review some of the current trends and innovations in the development of ADCs, focusing on three main aspects: linker technology, drug payloads, and manufacturing.
Linker technology
The linker is the molecule that connects the antibody and the drug payload. It plays a critical role in the efficacy, stability, and safety of ADCs. Ideally, the linker should be stable in the bloodstream, but cleavable inside the target cells to release the drug at the right time and place. There are diverse types of linkers, such as hydrophilic and hydrophobic, non-cleavable and cleavable, and heterobifunctional and homobifunctional. Each type has its own advantages and disadvantages, and the choice of linker depends on the characteristics of the antibody and the drug, as well as the desired pharmacokinetics and pharmacodynamics of the ADC.
Some of the recent advances in linker technology include conditionally active biologic (CAB) technology, which uses pH-sensitive linkers that are activated in the acidic tumor microenvironment; the development of site-specific conjugation methods, which allow the attachment of the drug to a precise location on the antibody; self-immolative linkers, which undergo spontaneous fragmentation after enzymatic cleavage; and dual-linker systems, which combine two different types of linkers to enhance the drug delivery and release. Also, there are recent innovations in linker technology improving the homogeneity and consistency of the ADC and the use of dual-linker systems, which combine two different types of linkers, such as a cleavable and a non-cleavable one, to achieve a more controlled drug release and a better therapeutic window.
Drug payloads
The drug payload is the cytotoxic agent that is delivered by the antibody to the target cells and in many cases killing the target cells. It should be highly potent, selective, and compatible with the antibody and the linker. It is usually a highly potent molecule that can induce cell death by interfering with various cellular processes, such as DNA synthesis, microtubule function, or protein synthesis. The selection of the drug payload depends on several factors, such as the target indication, the mechanism of action, the toxicity profile, and the compatibility with the antibody and the linker.
Some of the current trends in drug payloads include the development of novel classes of cytotoxins, such as DNA-alkylating agents, tubulin inhibitors, RNA polymerase inhibitors, and antibiotics. These new drugs offer different modes of action and higher potency than the conventional ones, such as maytansinoids and auristatins. Further new chemical entities, such as pyrrolobenzodiazepines, duocarmycins, and indolinobenzodiazepines5; and combination therapies, such as ADCs with immune checkpoint inhibitors, tyrosine kinase inhibitors, or radioisotopes6
Another emerging trend is the use of combination payloads, which consist of two or more different drugs that act synergistically or complementarily to enhance the efficacy and overcome the resistance of the ADC, such as ADCs with immune checkpoint inhibitors, tyrosine kinase inhibitors, or radioisotopes.
Manufacturing
The manufacturing of ADCs is a complex and costly process that requires specialized expertise, appropriate facilities, and equipment. It involves several steps, such as antibody production, drug synthesis, conjugation, purification, formulation, and quality control. Each step has its own challenges and risks, such as low yield, high variability, product degradation, contamination, and regulatory compliance.
Some of the recent innovations, trends, and improvements in manufacturing include site-specific conjugation platforms, such as enzymatic, chemical, or genetic methods, that can improve the homogeneity, stability, and potency of ADCs; the adoption of single-use technologies, which reduce the risk of cross-contamination and the need for cleaning and validation; and the implementation of continuous manufacturing processes, such as flow chemistry, that can increase the efficiency, scalability, and quality of ADCs Another emerging trend is the use of artificial intelligence and machine learning tools, that can optimize the design, development, and production of ADCs as well as the prediction and prevention of potential problems.
Conclusion
ADCs are a promising and rapidly evolving field of biopharmaceuticals that offer new opportunities and solutions for the treatment of various cancers especially those that are resistant to conventional therapies. They can enhance the efficacy and safety of existing therapies and can target novel antigens and mechanisms of action. However, developing ADCs is not a trivial task, as it involves many challenges and complexities. To overcome these hurdles, researchers and developers are constantly exploring and innovating new technologies and strategies in the areas of linker technology, drug payloads, and manufacturing. These trends and innovations are expected to improve the quality, safety, and efficacy of ADCs, as well as to reduce the cost and time of their development.
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Keywords:
Monoclonal Antibody, mAb, mammalian, bacterial, ADC, Antibody Drug Conjugate, linker technology, drug payload