April 7, 2014

Advances in Linker Technology: Improving the Safety and Efficacy of Antibody Drug Conjugates


The targeted delivery of cytotoxic drugs using antibody drug conjugates would not be possible without effective linkers to connect and then release the key chemical and biological materials.

With the approval of several antibody drug conjugates (ADCs) providing targeted delivery of cytotoxic APIs to specific sites of action, generally cancer cells at this point, their potential has been confirmed, and further investment in R&D has resulted.

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. “ADCs can, through the linkage of cytotoxic drugs to antibodies, safely deliver cytotoxic drugs that cannot be administered systemically because they are only released at the site of action, and it is the linker that makes this approach possible,” states Jonathan Drachman, chief medical officer and executive vice-president of R&D with Seattle Genetics.

Why use a linker?
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. “Antibodies have very long half-lives; they circulate in the blood stream for some time before they bind to and enter the target cell and then get into the lysosome, which generally is the target,” explains Clay Siegall, CEO of Seattle Genetics. 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. Stable linkers are dependent on lysosomal trafficking to release the cytotoxic payloads, and a certain percentage of the antibody never reaches the lysosome of the target cell, limiting the efficacy of stable linker compounds,” notes Hanspeter Gerber, vice-president of Pfizer. The linker, therefore, 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.

Matching chemistry and biology
Most importantly, according to Bob Hollingsworth, senior director of oncology research with MedImmune, the global biologics R&D arm of AstraZeneca, the linker makes it possible to match the chemistry of the payload with the biology of the antibody. Most linkers developed to date have been peptide-based. Initially, according to Gerber, the linker and antibody were bound together through hydrazone or disulfide bonds, which are sensitive to oxidative and reductive environments, respectively. However, there are reductive and oxidative environments in places other than inside of cells. Therefore, most linkers being developed today are designed to be selectively cleaved from the antibody by enzymes that are only present inside the lysosome where there is a low-pH environment, typically proteases or esterases, thus imparting intracellular biodegradability. “The challenge then, is choosing a linker chemistry that is stable chemically but sensitive to enzymatic cleavage, but only for these specific enzymes that are present in tumor cells,” says Thomas H. Pillow, ADC chemistry team leader with Genentech, a member of the Roche Group.

For the ADC technology used in ADCETRIS, Seattle Genetics has also found that it is necessary to include a “spacer” between the bond to the antibody and the peptide portion of the linker, according to Drachman. “This structural spacer is needed to provide room for the enzyme to recognize and bind to the cleavable portion of the linker,” he explains. The linker that the company developed for ADCETRIS, its ADC linker commercialized in collaboration with Takeda Pharmaceuticals and approved in more than 35 countries for the treatment of relapsed Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma. Large cell lymphoma is comprised of valine and citrulline with structural spacers on each end. Once the linker is cleaved from the antibody, the spacer undergoes self-immolation, resulting in the release of the small molecule drug without attachment to any linker components.


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Tags: linker, ADC, antibody drug conjugate