Raffinose acts as a competitive inhibitor for a specific transferase in the Golgi, which slows, rather than blocks, the glycan branching process. This results in the enrichment of Manos-5 species, a different outcome than the Manos-8/9 glycans produced by a complete block with inhibitors like kifunensine.
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The company focuses on disease-specific 3D protein conformations, which exposes new binding sites (epitopes) not present on the same protein in healthy cells. This allows for highly selective drugs that avoid the toxicity common with targets defined by genetic sequence alone.
Different TROP2-targeted ADCs using the same class of payload (topo-1 inhibitor) display distinct primary toxicities, such as diarrhea versus stomatitis. This highlights that subtle differences in drug-to-antibody ratio and linker technology create unique pharmacological profiles, making the drugs clinically distinct despite their apparent similarities.
The industry's focus on antibodies, which are easy to generate, may be a case of technology dictating the science. Dr. Radvanyi argues that natural ligand-receptor interactions, which often rely on lower affinity and higher avidity, could offer a more nuanced and effective way to modulate immune pathways than high-affinity agonist antibodies.
Butyrate, a short-chain fatty acid from gut bacteria, functions similarly to HDAC inhibitor drugs used in cancer therapy. This provides a scientific mechanism for how diet impacts myeloma, revealing its role in anti-tumor and anti-inflammatory pathways.
A-muto suggests many drug programs fail due to toxicity from hitting the wrong epitope, not a flawed biological concept. By identifying and targeting a structural epitope unique to the diseased state of the same protein, these previously abandoned but promising therapies could be salvaged.
Unlike the complex fibers from whole foods, purified prebiotics can cause a bloom of a small number of bacteria specialized in consuming that single fiber type. This can lead to an overall decrease in microbial diversity as these few specialists outcompete other microbes. A wide variety of plant foods is a safer approach to fostering a diverse gut ecosystem.
Initial experiments failed because adding raffinose also increased osmotic stress, killing cells. The breakthrough was maintaining constant osmolality by adjusting NaCl as raffinose was added. This isolated the specific effect of raffinose on glycan profiles, revealing a clear dose-response relationship without harming cell viability.
Using raffinose to adjust glycosylation is a regulatory-friendly strategy. Since it is a simple media component adjustment, not an enzyme inhibitor or genetic modification, it aligns with standard process development activities. This avoids intense scrutiny and justification required for more complex methods, simplifying the CMC package.
Antibodies bind to specific amino acid sequences, making them unable to distinguish between a protein's healthy and toxic structural forms. Alt-Pep's synthetic peptides use a complementary structure (alpha-sheet) to selectively bind only the toxic oligomers, enabling both targeted therapy and highly specific diagnostics.
Dr. Radvanyi explains that immune agonist drugs often fail because accelerating a biological pathway is inherently less controllable than inhibiting one. This is analogous to genetic knockouts being more straightforward than over-expression models, presenting a core challenge in drug development beyond just finding the right target.