Bristol-Myers Squibb has two different research collaboration and licensing deals, one with SyntheX in San Francisco and the other with Autolus Therapeutics in London.
SyntheX’s ToRNeDO platform will be used in this first partnership to break down proteins. The platform finds molecular glue-based protein degraders by using E3 ligases and new substrates that have already been chosen.
Molecular glue degraders are chemicals that help a target protein and an E3 ubiquitin ligase work together to break down the target protein.
Ubiquitin sticks to old proteins and tells cells that it’s time to get rid of them by breaking them up into their individual molecules.
BMS is giving cash upfront and putting money into the company. Synthes could get up to $550 million in milestone payments based on how well it does. It can also get royalties based on the net sales of any commercial products that come after it.
BMS Invests in Protein Degradation,
Maria Soloveychik, Ph.D., co-founder, and CEO of Synthes, said that the company is excited to combine its ToRNeDO platform with BMS’s expertise in clinical development as “we work to find and give patients in need the next generation of TPD therapies.”
Focusing on oncology, the company’s pipeline includes STX100, which targets RAD51; STX200, which targets RAF1, STX300, which targets KRASG122X, STX400, which targets NRas, STX500, which targets Cbl-b, and STX600, which targets Shoc2. All are in preclinical development.
BMS, SOSV, OMX/Ventures, MorganNoble, Oriza Ventures, and 8VC are all investors in Synthes.
The agreement between BMS and Autolus Therapeutics gives BMS access to Autolus’ RQR8 safety switch, which BMS can then use in certain cell therapies for cancer.
Cell therapies often have dangerous side effects, such as cytokine release syndrome and brain toxicity. In these kinds of cell therapies, like CAR-T, T-cells are genetically modified to respond to specific cancer antigens and their epitopes. They are then put back into the patient, where they become a living therapy that makes more T-cells attack the cancer cells.
But they can grow too quickly or too much, which can lead to serious problems. Safety switches like Autolus’s RQR8 can limit these side effects by putting limits on how many T-cells can be made.
In a prepared statement, Martin Pule, CSO of Autolus, said, “Safety switches are very important to the future of our field of advanced cell therapies.” “They let us come up with ways to treat patients that are meant to make a big difference in how well they do while also lowering the risk that they will have bad side effects from the treatment.”
Rituxan from Genetech and Biogen is given along with Autolus’s RQR8 switch (rituximab). Rituxan has been approved to treat non-lymphoma, Hodgkin’s chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus Vulgaris.
When rituximab is given in the right amount, it binds to the engineered CD20 epitopes on the surface of the cell therapy and causes only some of the cells to die. RQR8 is a marker/suicide gene that is based on an epitope of 136 amino acids.
A suicide gene is coded in the DNA so that it only kills the transferred T cells when the level of toxicity is too high. This is a common and serious side effect of CAR-T and other cell therapies.
In particular, RQR8 is for T-cells and combines target epitopes from both CD34 and CD20 antigens. This allows selection from a clinically approved CliniMACS CD34 system (Miltenyi), a medical device system designed to enrich CD34+ targets. By binding to rituximab, it deletes transgene-expressing cells in a targeted way.
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