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Innovative Linker Technology for Antibody Drug Conjugates (ADCs)
The ever-growing sophistication and variation in linker design have given rise to a new and distinct field of knowledge in synthetic chemistry. Recent developments in combination therapy, antibody-drug conjugations (ADCs), is based on linking together two compounds with different functionalities. After a decade-long trickle of ADCs, the US Food and Drug Administration approved three new ADCs in 2019 and one in 2020 to treat various cancers. That burst of activity brought the total number of FDA-approved ADCs on the market to eight, a definite uptick to end the decade.
ADCs consist of an antibody, a pharmaceutically active small molecule drug or toxin (i.e., the payload), and a linker to connect the two. The linker, typically a peptide derivative, joins the small-molecule, highly potent drug to the large-molecule antibody, which is selected or engineered to target the antigens on a specific type of cell. In the development of ADCs, the design of linkers is essentially important, because the linker impacts the efficacy and tolerability of ADCs.
1. Why Use Linkers?
An ADC is effective only if it delivers the cytotoxic payload to the target cell. If the drug is released too soon, it can cause harm to normal cells. That means it must be stable until the ADC enters the target cell, but then allows release of the payload in a manner that maintains the reactivity of the cytotoxic therapeutic. "We want to kill tumor cells, but we don't want to harm the nontumor cells, and at the moment, that's still a challenge," said David Satijn, vice president of new antibody products, Genmab. Therefore, the attachment of payloads directly to antibodies using a stable linker has been investigated, but the performance seems to vary depending on the cell surface target selected. The linker is necessary to control the release of the cytotoxic within the target cells outside of the lysosome without being released in non-targeted tissues or during circulation, to ensure both increased safety and efficacy.
2. Types of Linkers
According to the different mechanisms of drug release, linkers in ADC development can be classified into two categories: cleavable linkers and noncleavable linkers. Cleavable linkers rely on the physiological stimuli, which mainly include chemically cleavable linkers and enzymatically cleavable linkers. Chemically cleavable linkers including acid-labile linkers and disulfide linkers are popular in the ADC clinical pipeline. For acid-labile linkers, intracellular release of payloads relies on the different pH between endosomes/lysosomes and blood. The release of disulﬁde-linked drugs is controlled by the factors in intracellular environment. Enzymatically cleavable linkers, peptide linkers and β-glucuronide linkers, are sensitive to enzymes located in cytoplasm. Alternatively, noncleavable linkers require proteolytic degradation. They depend on the internalization more than cleavable linkers do. In ADC development, several noncleavable alkyl and polymeric linkers have been explored. Different linkers have their advantages and limitations. Ultimately, the choice of the linker is unique tailored to the correlate antibody, drug and the disease to be treated.
3. Attachment Sites on the Antibodies for Linkers
The sites within the antibody to which the linker is bound to affect the performance of an ADC. It is most common to connect the linker to the antibody via reaction with amino acids, with cysteine the most common, followed by lysine.
Tweaking the sites where the linker and the payload attached to the antibody has been an area where many ADC makers are working. Except for Enhertu, all the FDA-approved ADCs are heterogeneous: the number of linker-payload groups attached to each antibody varies. Creating homogeneous ADCs, in which each antibody connects to the same number of payload-linker groups, has been an area of intense research.
ADC makers initially turned to lysine or cysteine groups on the antibody to attach the linker and payload. But they are increasingly engineering specific sites onto antibodies to make those connections. These site-specific, homogeneous ADCs have the potential to perform better than heterogeneous ADCs. That's because the homogeneous ADC is just one molecule rather than a group of molecules, so the biophysical properties are more uniform.
Catalent developed SMARTag technology to create site-specific homogeneous ADCs. SMARTag was originally developed at Redwood Bioscience, which was acquired by Catalent Pharma Solutions in 2014. The method creates sites for attaching linker-payload groups to antibodies by encoding a string of six amino acids into the antibody. As the antibody is made, a formylglycine-generating enzyme recognizes that string and converts its cysteine into an aldehyde-containing formylglycine.
By using that aldehyde, scientists can forge a C–C bond between the antibody and the linker-payload group. Triphase Accelerator recently licensed an ADC made using this technology, called TRPH-222. It's in Phase 1 clinical trials for non-Hodgkin's lymphoma.
As data for that drug and others in the pipeline emerge, the field will start to understand whether these chemical advances can make ADCs more effective.
4. Future expectations
Given the potential for ADCs to provide the targeted delivery of highly potent drugs, it is not surprising that many pharmaceutical companies are working with biopharmaceutical companies focused on linker and conjugation technologies to build a pipeline of ADC candidates. It's a good modality, but it's a complicated one, so there's been a lot of learning. Eventually, we'll be seeing more and more approvals. Newer technologies are going to be helpful to overcome some of the problems that led to clinical failures.
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