MODULATING ANTIBODY ACTIVITY USING CHEMICAL BIOLOGY

Therapeutic monoclonal antibodies have transformed medicine, especially with regards to treating cancers and disorders of the immune system. More than 50 antibody-derived drugs have already reached the clinic, the majority of which target cytokines or cell-surface receptors. Unfortunately, many of these targets have “pleiotropic” functions: they serve multiple different roles, and often not all of these roles are disease-related. This can be problematic because antibodies act throughout the body, and systemic neutralization of such targets can lead to safety concerns. Drawing from tumor necrosis factor α (TNFα) as an example, several therapeutic antibodies have been approved for use in relieving disease-associated inflammation stemming from overproduction of TNFα, but each of these comes with well-known safety risks since this cytokine is needed as a first line of defense against infections.

We have developed an approach called “chemical rescue of structure” to introduce allosteric control of protein activity through a designed ligand-binding site, and have begun applying it to antibody structures. Briefly, we introduce a pair of adjacent cavity-forming mutations between the variable domains that disrupts their relative orientation, and thus their antigen binding. Upon subsequent addition of a ligand that complements this hole, the orientation of the variable domains is restored and antigen-binding is thus recovered.

Moving forward, we expect that this approach can be directly applied to develop a new class of antibody reagents with activity that can be localized through their dependence on the presence of an activating ligand. This, in turn, may enable safe and effective local neutralization of TNFα, as well as other pleiotropic cytokines and cell-surface receptors.