Conventional anti-cancer therapeutics are characterized by on-target-off-tumor toxicities, which renders them harmful to patients. Such concerns were instrumental in paving the way for targeted therapies. Antibody drug conjugates are a complex and versatile form of anti-cancer therapy, which have been proven to be more effective and less toxic to patients. Such interventions are designed to identify specific antigens that are expressed on the surface of cancer (target) cells so that the effects of the cytotoxin / drug are focused on the elimination of only the cancerous cells. Owing to the target specificity component, the approach reduces the chances of damaging normal cells. Over the years, this class of therapeutics has undergone several improvements, most of which were focused on how the highly potent cytotoxic component could be attached to the segment that confers specificity (the antibody). The physical attachment of the aforementioned components is facilitated in a process that is commonly referred to as conjugation, or bioconjugation. This chapter features brief descriptions of the different types of linker and conjugation technologies that are used in the development of ADCs. Further, it offers insights from the industry’s perspective, concerning the future of these technologies. The global ADC technology market is anticipated to grow at a CAGR of around 15%, till 2035, according to Roots Analysis. With the growing focus on development of efficacious and site selective drug, the ADC linkers and conjugation technologies market is anticipated to grow at an exponential rate.
ANTIBODY DRUG CONJUGATES OVERVIEW
Antibody drug conjugates (ADCs) are an upcoming class of targeted therapeutic agents. Fundamentally, these complex biotherapeutic entities demonstrate the combination of target specificity of an antibody and therapeutic features of a chemotherapy / cytotoxic drug. They are believed to be more efficient and effective in specifically identifying and eliminating cells / pathogens that are associated with the disease(s). Further, it is important to mention that the efficacy of an ADC depends on the choice of antibody and cytotoxic payload.
ADCs consist of an antibody and a small molecule drug that are linked through a molecule, called linker. Even though both the molecules can be separately used as viable therapeutics, together, they become a guided therapeutic entity. Interestingly, the mechanism of action of the conjugate is completely different from that of the individual components.
Antibody: The antibody is usually of monoclonal origin, which identifies and binds to a specific receptor on target cells. These are used to specifically target the aberrant cells in cancer and other diseases. Thus, the main function of the antibody component in an ADC is to guide the conjugate molecule to the target cells.
Cytotoxin: The drug, also referred to as cytotoxin, may be an antibiotic or any other agent that has the capability to either treat or cause the death of a diseased / transformed cell. Various research studies have suggested that less than 0.1% of the injected ADCs is actually taken up by the target cells.
Linker: The antibody and the cytotoxin are conjugated through a synthetic chemical linker, which ensures the integrity of the conjugate after its administration into the body. The stability of the linker affects the efficacy and potency of the ADC molecule. It is essential that the linker remains stable in the bloodstream and gets cleaved to release the drug only when the complex is inside the target cell.
ADC LINKER TECHNOLOGIES
Early linkers, which were derived from the acid cleavable hydrazones, could be cleaved at non target sites and thereby, were known to cause systemic toxicity. To overcome these challenges, second-generation linkers, with improved stability, were developed. Examples of second-generation linkers include disulfide linkers, peptide linkers and thioether linkers. More recently, third generation ADC linkers have been developed to target drug-resistant tumor cells. PEG4Mal linker is an example of such linker.
Linkers are generally manufactured through legacy synthetic chemistry processes. Therefore, the production of such molecules is not technically demanding, and does not require specialized facilities (as is necessary for cytotoxic drugs), or clean rooms / aseptic production environments (as is required for antibodies). Therefore, it is relatively simple for any contract manufacturer to manufacture such chemical entities for conjugate drug development purposes.
Further, the use of different types of linkers plays a significant role in determining the pharmacokinetic properties, selectivity, therapeutic index, efficacy and the overall stability of ADCs. The two major types of linkers include non-cleavable linker and cleavable linker.
- NON-CLEAVABLE LINKERS: Non-cleavable linkers release the cytotoxic entity during the lysosomal degradation of the ADC inside the target cell. These linkers are comprised of thioethers as the key chemical group. These linkers are capable of facilitating the alteration of the chemical properties of the small molecule to improve the efficacy of the ADC. In contrast to cleavable linkers, non-cleavable linkers have higher plasma stability and a wider therapeutic window owing to ability of the payload derivative to kill the target cells.
- CLEAVABLE LINKERS: Cleavable linkers are designed to undergo specific release mechanisms due to the differences between the extracellular and intracellular environments allowing controlled cleavage at the target sites. Owing to their stability in systemic circulation and efficiency of getting cleaved upon internalization, cleavable linkers have played an important role in the success of ADCs.
Conjugation is referred to as the covalent derivatization of biomolecules, such as proteins, nucleotides or polysaccharides to a synthetic or semisynthetic molecule, including drugs, carbohydrates, peptides and other bio- or synthetic polymers. Drug conjugates represent a growing class of targeted therapies designed to increase target selectivity, the potency and/or efficacy of anticancer therapy, to overcome low efficacy, drug resistance, and/or toxicity associated with single drug use or monotherapy. Likewise, there is a growing trend towards endowing the antibodies as immunoconjugates with enhanced therapeutic efficacy. For tethering the antibody to the payload, ADC developers either use their proprietary conjugation technology or license the same from a technology provider. These technologies either facilitate chemical conjugation or enzymatic conjugation. The various types of conjugation include:
- CHEMICAL CONJUGATION: Chemical conjugation involves different chemical reactions between the amino acids present on the antibodies and the linker molecule carrying the payload. The process results in conjugates with variable drug to antibody ratio (DAR) values. Furthermore, it is important to mention that this conjugation employs different techniques, such as lysine coupling, cysteine coupling and incorporation of non-natural amino acids by genetic engineering.
- ENZYMATIC CONJUGATION: In this type of conjugation method, enzymes are used to link antibody and payload. There are three different methods available for enzymatic conjugation, which use various enzymes, such as sortase, transglutaminase and N-glycan. These methods are used for site-specific conjugation and ADCs with controlled DAR values.
It is evident that the evolutionary advances in conjugation and linker technologies have enabled the development of viable treatment options. Such improvements have significantly altered the therapeutic potential and likely applications of ADCs.
Despite the current opinion on the superiority of this class of therapeutics, the existing understanding of the biochemical, immunological, pharmacological, and molecular aspects of ADCs needs to be furthered in order to design and develop better versions of these products. As a result, there are a number of efforts directed towards the development of better / more stable linkers and site-specific conjugation methods that enable manufacturers to synthesize homogeneous batches of ADCs.
The demand for ADCs is on the rise. In this context, it is important to mention that ADCs have also been proven to be more effective in treating bacterial infections than conventional antibiotic-based treatment regimens. Another popular field that has emerged as a potential application area for ADCs, is chronic clinical conditions. In this case, selective payload delivery, using ADCs, to disease-associated biological targets has been demonstrated to reduce side-effects. In terms of novel treatment paradigms, ADCs are also being investigated in combination with small-molecule drugs. The growing popularity of this approach can be attributed to its potential to overcome the concerns related to multi-drug resistance. With the growing demand for ADCs, therapy developers, as indicated earlier, are striving to discover and develop better conjugation methods and the means to further tap into the vast potential of these therapeutics.
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