Seattle Genetics has developed a technology using synthetic agents called auristatins and linker systems that attach these auristatins to antibodies. The linkers are designed to be stable in the blood and release a potent cell-killing agent once inside the target cell. This approach was designed to reduce toxicity of traditional chemotherapy while enhancing antitumor activity.
Challenges in formulation development, said Shan Jiang, Ph.D., director of formulation, are due to the complex nature of antibody-drug conjugates (ADCs). Attaching various cytotoxins to the antibody can alter stability and solubility. It’s important to understand degradation pathways and evaluate physical and chemical instability of molecules.
“One needs to pay close attention to the quality attributes unique to ADCs such as drug-to-antibody molar ratio, sites of drug conjugation, conjugation drug-related impurities, and potency.”
The company has also developed various analytical methods to better develop ADCs. SGN-35 (brentuximab vedotin), one of its ADCs currently in clinical trials, has shown “encouraging activity in early-stage trials in Hodgkin lymphoma and anaplastic large cell lymphoma patients refractory to several forms of chemotherapy,” reported Peter Senter, Ph.D., vp, chemistry.
According to Dr. Senter, a specialized linker technology was developed for its auristatins, a class of antitubulin drugs that includes monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). “The linker incorporates conjugation technology that allows the drug to be attached to the antibody in a way that does not affect its pharmacokinetic properties.”
The combination of the drug, linker, and conjugation technology, along with the antibodies being used, has contributed to the positive results seen in the clinic to date, Dr. Senter said. He added that the technology is applicable to a wide variety of malignancies, and is also currently in trials for solid tumors with various antibodies.
“We found that the drug-linker technology we developed applies to almost all antibodies that we’ve looked at—and we’ve looked at hundreds.”
Although Seattle Genetics has studied its technology with artificial constructs called diabodies, Dr. Senter reported that they have no reason to believe those novel scaffolds will be better than antibodies for drug delivery. “Antibodies are ideally suited for what we’re doing because they stay in circulation a long time and are stable—they are close to ideal carriers for drugs.”