Discovery of new protein could revolutionize cancer drug delivery

The nice thing about being an academic is that I can investigate anything I find to be interesting, regardless of the field. One would have to have a fairly limited imagination to focus on only one thing your entire life. Discoveries in one area usually impact other areas, so a new analytical method can be used in many fields. Once you invent a new method or a technique, even the most limited researchers can and do use it in many important fields. It is the invention of the new effective technique that mattered.

What we're trying to do here at Benevolent is develop systems and processes that allow us to tap into the huge amount of public information and some propriety databases that we have paid to access and through that, generate hypotheses which our scientists can then triage. We've got over ten times the amount of information in our database at present (and it’s growing) than we believe that companies such as Watson have. Bringing that and filtering the signals from the ‘noise’ to our experienced drug discovery chemists and biologists, means, firstly, we can reduce the amount of time we take to triage new hypotheses, and secondly, we can develop more predictive chemical tools to allow us to make better molecules and also to reposition existing molecules for new indication.

The CAR positive rate is a critical metric for evaluating CAR-T product potency, directly influencing target recognition and cytotoxic efficacy. Monitoring CAR expression in peripheral blood or tissues post-infusion provides insights into in vivo expansion and persistence, informing treatment response, durability, and potential relapse risk. Dynamic CAR expression monitoring also helps assess immunogenicity and safety. Thus, a sensitive, reliable, and universal CAR detection system is vital for developing and evaluating CAR-T cell therapies. Currently, approved CAR-T products target CD19 or BCMA, making flow cytometry with recombinant BCMA or CD19 protein the standard detection method. Although highly specific, this approach is limited to single targets and is unsuitable for CAR-T screening and preclinical development. Several CAR detection methods have been developed, including Protein L (which binds immunoglobulins) or Fc-binding polyclonal antibodies. Protein L binds only to kappa light chains and fails to detect CARs containing lambda chains. Polyclonal antibodies may cross-react with patient IgG, causing false positives. Anti-idiotype antibodies offer high specificity and sensitivity by targeting unique idiotopes in the CAR's antigen-binding region, but they are challenging to develop and produce.

Dr. Mills first evaluated the activity of COTI-2 in a number of human cancer cells lines that we had not previously studied. He was able to evaluate the killing activity of COTI-2 in the context of p53 mutations since the p53 mutation status of these cells was known. He then went on to introduce 32 different types of p53 mutations into mouse embryonic fibroblasts (MEFs), a cell-based system for studying the effect of gene mutations. Once the p53 gene mutations were established in the MEFs the effect of COTI-2 on those cells was evaluated. Changes in normal p53 protein levels together with changes in other proteins known to be direct cellular targets of normal p53 protein were also evaluated for each of 32 different types of p53 mutations following treatment with COTI-2.

As an analogy, when the axon is scaled up to be the arm in a human body, you can think of the axon length in relation to the neuron's cell body as the equivalent distance from Nottingham to Paris. This significant length poses a logistical challenge for the neuron. For proteins to be expressed at the axon terminal, which is distant from the cell body, there's a requirement for translation regulation. In other words, there is a need for descentralized gene expression. Here, small non-coding RNAs play a pivotal role. Our work on microRNAs has shown their importance in spatial-temporal control of gene expression. This research aligns with the current interest in RNA biology and offers potential avenues for drug discovery, especially given the advances in RNA technologies post-covid.