Intracellular antibodies and biodegraders: Beyond small molecules and back again

Intracellular antibodies have been deployed as powerful research tools for the last 20 years for inhibition of proteins to convey specific information about protein function. Accordingly, intracellular antibodies have been used for target validation in oncology and were the first reagents to inhibit “undruggable” targets, such as RAS mutants and LMO2. Their versatility allows addition of effector functions to invoke cell phenotypes following target engagement inside cells. Moreover, the paratope–epitope interaction of intracellular antibodies has been recently exploited to develop small molecule surrogates. We will discuss the flexibility that intracellular antibodies provide for discovery research and for new generations of therapeutics in all clinical indications where an aberrant protein expression is involved (oncology, neurological disease, infection, inflammation).