Dr. Papo’s lab uses both combinatorial library screening and computational methods to develop high affinity proteins against different disease-related targets such as cancers, bone diseases, and neurodegenerative diseases. Ultimately, the basic science is studying protein-protein interactions.
The research team makes mono and multi-specific proteins that are alternatives to antibodies that can target single or multiple receptors (soluble or membrane-anchored) that are overexpressed in disease but not normal cells.
Dr. Papo and his team screen the protein pool against a specific target (in the presence of other related targets so that they can choose and select only binders to the specific target) and in doing so they make selective drugs and enhanced imaging agents for PET scanning.
If the targets promote metastasis, the drugs (i.e., their modified protein) antagonize the action of the targets, replacing the natural, biological ligand, resulting in inhibition and a therapeutic effect. These drugs can also be labeled with dyes or radioactive isotopes, and used for imaging.
Any structural protein can, in theory, be used to bind to any desired target, and the researchers use small human proteins so that they are not toxic or immunogenic, and can penetrate a tumor with ease. Dr. Papo and his team randomize the sequences, make a library, and screen for good binders, though we also use rational approaches, too, looking for some degree of initial binding – it is easier to enhance binding than to create binding from nothing.
For example, matrix metalloproteases (MMPs) are a class of proteins found in a variety of states – some are beneficial while others may cause cancer. The researchers target those that cause cancer but all of the proteins are very similar in structural terms, so they must make a selective protein that binds one MMP but not all. The group focuses on TIMPs, natural inhibitors of MMPs, but since these bind and inhibit all MMPS, they have developed a method to make a new protein that is selective and binds to only one desired MMP. In some cases, an improvement in the binding kinetics on the scale of three orders of magnitude is observed.
The lab also works to improve the pharmacokinetic profiles of their agents.