Enhancing Antibody-Drug Conjugates
There are three main challenges in developing antibody-drug conjugates, said John Lambert, Ph.D, executive vp of R&D and CSO at ImmunoGen. First, the antibody must be optimized for a given target. This takes into account how fast the antibody target is internalized and the route of internalization.
“Different antibodies binding to one target can influence the intracellular trafficking routes and perhaps the rate at which all those events occur.” Then the correct payload-linker combination must be selected.
“Different targets sufficiently traffic to lysosomes, where a noncleavable link would be appropriate. But, there are targets that do not traffic to lysosomes well and this would require a different linker.” A way to approach this is to make various compounds with different linker payload combinations and test them. The payload has to be potent. Two payloads that have yielded good activity on the tumor and are nontoxic and stable are maytansinoids and aurestatins.
“We think that each component is important and have learned a great deal about antigen selection and the nature of the antibody. One of the reasons we use a modular approach to our linkers is to allow for testing of different designs.”
The company’s approach to linker technology, called TAP, uses surface-accessible amino groups to avoid disturbing the structure of the antibody and, thus, yield stable compounds. Dr. Lambert explained that new linkers being developed include several with hydrophilic characteristics. When these are part of the linker, the payload linker lysine released in the cell can kill the cell, but also resists efflux pumps by multidrug resistance (MDR).
According to Dr. Lambert, these new linkers may allow for targeting of tumors that have a propensity to become resistant to chemotherapy.
Formulation challenges include distinguishing events that shorten shelf-life, which are antibody-specific versus those that are the properties of the ADC itself.
There are currently three different maytansinoid-linker compounds in clinical trials. “The exact property of a linker depends on the biology of the target and target cell. There isn’t a one-size fits all,” Dr. Lambert said.