Watertown Bio Journal Club - How Many Ways Can You Break a Protein?
Talking about proteases, PROTACs, and molecular glues. Plus new methods for mass spec tagging, viral inhibitors, and more.
Featured Article: Therapeutic IgG- and IgM-specific proteases disarm the acetylcholine receptor autoantibodies that drive myasthenia gravis pathology
In their article published in PNAS, Seismic Therapeutic describes one of their lead therapeutic candidates S-1117, a pan-IgG protease, and its potential therapeutic use to cleave the acetylcholine receptor (AChR)-targeted autoantibodies that cause myasthenia gravis (MG). Using both recombinant AcHR targeted antibodies and patient serum samples, they demonstrated S-1117’s ability to cleave IgG antibodies and reduce compliment deposition in cell based assays. They also characterized a subset of patient samples with AcHR-IgM antibodies that mediates compliment deposition, and replicated their IgG findings by using an IgM specific protease to cleave the IgM autoantibodies and reduce compliment deposition, providing additional evidence that multiple classes of autoantibodies can can drive compliment activation in MG .
From a technical perspective, the group explored unexpected results where reduction in compliment deposition was higher with serum samples than with monoclonal antibodies after cleavage with S-1117. They provide evidence that this is due to the uniform antigen specificity found in monoclonal antibody samples, compared to the polyclonal patient serum samples. After cleavage, the high levels of identical monoclonal AcHR-specific F(ab′)2 interact with anti-F(ab′)2 antibodies to activate compliment deposition, while in the polyclonal serum, the variety of available cleaved fragments reduce the chances of an AcHR-specific F(ab′)2 complex forming. Coming from an experimental cell biology background, I appreciate their consideration of the tools and reagents used to model MG, and how those choices affected experimental outcomes.
In addition to this article, Seismic also shared a poster at ACR Convergence highlighting S-1117, and a poster describing their bi-functional PD-1:FcγRIIb antibody S-4321.
Related Protein Degrader Posters:
Kymera Therapeutics shared two posters from ACR Convergence where they used their KT-579 PROTAC to degrade IRF5 in Lupus and Rheumatoid Arthritis mouse models.
C4 Therapeutics shared a poster from Targets 2025 where they developed a population pharmacokinetic model for their molecular glue IKZF1/3 degrader cemsidomide, using data from their phase 1 trial of cemsidomide in patients with multiple myeloma.
Featured Preprint: How to design 1000-plex mass tags using the differential mass defect
In their preprint shared on bioRxiv, Parallel Squared Technology Institute, a non-profit FRO focused on increasing mass spectrometry throughput, shared their framework for using the differential mass effect to generate large numbers of mass spec tags using careful combinations of a few small molecules. The differential mass effect takes advantage of the difference in masses between molecules of the same chemical structure, with the same number of protons, neutrons, and electrons, but different elemental isotopes. Using this principle, they designed several theoretical mass spec tags and developed rules for scaling the number of available tags to potentially multiplex thousands of tags without needing a different synthesis route for each individual tag. With a theoretical framework in place, it will be interesting to see what experimental throughputs can be achieved using these tags.
Inhibitors Roundup:
Acrivon Therapeutics shared a trio of posters from Targets 2025 highlighting their clinical stage WEE1/PKMYT1 checkpoint inhibitor ACR-2316, the computational modeling behind its design, and its mechanism of action.
At IDWeek 2025 Enanta Pharmaceuticals shared a presentation and a poster demonstrating the phase 2a trial results of EDP-323 an L-protease inhibitor, as a post-exposure prophylactic for RSV. They also shared a poster highlighting their phase 2 trial results of EDP-938 (Zelicapavir), an n-protein inhibitor for RSV.
At the American Academy of Ophthalmology Annual Meeting, Eyepoint Pharmaceuticals shared a presentation with phase 2 trial results for EYP-1901(DURAVYU), a biodegradable intravitreal insert for continuous release of the VEGF inhibitor vorolanib to treat wet age-related macular degeneration and diabetic macular edema.
Nucleic Acid Editors Updates:
Prime Medicine (headquartered in Cambridge but has a lab in Watertown), shared a number of posters with program updates at the European Society for Gene and Cell Therapies Congress, including updates on their lead compound PM359 for the treatment of Chronic Granulomatous Disease and Wilson’s Disease, methods for predicting off-target prime editor effects, computational methods to predict prime editor outcomes, non-viral generation of CAR-T cells using prime-editors and recombinases/integrases (which starts to cross over into the same space as Averna Therapeutics’ retrotransposon technology.)
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