Using mAbs to Access Undruggable Targets

Although monoclonal antibodies (mAbs) are valuable sources for the treatment of chronic conditions, mAbs do not generally penetrate into cells, a fact that limits their efficiency, David Scheinberg, MD, PhD, chair, molecular pharmacology and chemistry program of Sloan Kettering Institute and director of the Center for Experimental Therapeutics, said during a presentation at BIO 2015.

Most proteins are not druggable currently, Scheinberg noted. Nearly all drugs target less than 2% of cellular proteins and only five classes of proteins, he added. To increase specificity and potency, mAbs can be linked to alpha-emitting particles to more easily target intracellular oncogenic proteins.

Scheinberg’s lab is focused on a few projects dealing with a molecular nanogenerator that release alpha particles inside cancer cells. The lab is specifically investigating the use of actinium-225 coupled to internalizing monoclonal antibodies and researching the use of a molecular nanogenerator that releases alpha particles inside cancer cells to kill them.

In his BIO presentation, Scheinberg also described the engineering of a bispecific T-cell engager (BiTE) that can bind T cells to tumor cells and induce immune-mediated tumor cell destruction. BiTEs, a class of bispecific mAbs, bring T cells to the surface of cells, and are designed to target tumor-specific intracellular antigens. In addition, BiTEs have been shown to have vaccine-like effects; T cells are “educated” to recognize a specific antigen, according to Scheinberg. A paper on the topic, discussing the engineering of the first T-BiTE derived from a TCR-like mAb, is scheduled to be published in an upcoming issue of Nature Biotech.

According to Jan Reichert, managing director at Reichert Biotechnology Consulting, six new (i.e., never before approved in US) mAbs were approved by FDA in 2014. A total of seven new mAbs are currently undergoing review by FDA.