Many cancer-driving proteins sit inside cells, locked away from the antibody drugs that could disable them. A team has discovered carrier molecules—called TriTats—that can hitch antibody fragments to these proteins, and now aims to turn those fragments into "biodegraders" that mark the targets for destruction by the cell’s own waste-disposal machinery. This matters because most cancer targets inside cells are considered "undruggable": small molecules often fail to block protein-protein interactions or hit transcription factors lodged in the nucleus. Antibodies can do the job, but they cannot naturally cross cell membranes. The TriTat carriers solve that entry problem. The researchers are first testing the approach on T-cell acute leukaemia (T-ALL), a hard-to-treat blood cancer with no effective options once it relapses, especially in older patients. If successful, this technology could open an enormous range of cancer-drugging capabilities. By delivering antibody biodegraders systemically—through the bloodstream—it would allow doctors to degrade previously untouchable proteins inside cancer cells anywhere in the body. The work is preclinical, using mouse models to evaluate pharmacokinetics, but it is a direct step toward clinical application in patients.
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Most cancer targets are within the cell and are undruggable or hard-to-drug when proteins are inaccessible because of protein-protein interactions, or because these are transcription factors lodged in the nucleus or post-translationally modified. It is difficult to develop small molecule drugs against these types of proteins but there are examples of protein macromolecules, such as antibodies or antibody fragments, that are potent inhibitors of their molecular targets which have been used, for example, in target validation studies. The problem with such macromolecules as drugs per se is that they do not naturally enter cells. The long term, major objective is to develop and hone technology to efficiently deliver antibody fragments that are directed against critical drivers of the malignant phenotype into cancer cells in any situation in the body. The problem to solve is the effective delivery of antibody fragments into cancer cells in patients. A recent step forward is our discovery of new carrier molecules, called TriTats, that when bound to antibody fragments act as vehicles for entry into cancer cells. We propose to develop a novel combination in which antibody biodegraders are coupled to these internalisation vehicles for a new drug pharmacology applied firstly to T cell leukaemia but which will be applicable across other cancers. We are focusing on T cell acute leukaemia (T-ALL) initially because it is hard to treat, especially in older patients where thymus-derived cells are lacking, and when the cancer relapses there are no effective current treatments. In addition, cancer cells, in bone marrow, blood and peripheral lymphoid organs, are accessible to antibodies in the circulation and there has been considerable success with targeting macromolecules to key proteins in this cancer. To render the internalising antibodies more effective we will employ protein engineering to significantly enhance the potency of intracellular fragments of antibodies (iDAbs) to convert them to biodegraders by fusing directly to E3 ligase components. This will cause target protein degradation by the proteosome as a result of binary interaction of the biodegrader and the target antigen. Preclinical mouse models will be used for evaluating pharmacokinetics and pharmacodynamics of entities comprising internalising biodegraders. This will be a prelude to clinical application in cancer patients. Our work will produce technologies for internalisation of antibodies delivered systemically and will translate to clinical application, opening an enormous range of cancer drugging capabilities.
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