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.
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Previous IL-2 therapies from companies like Nektar and Synthorix broadly targeted beta and gamma receptors, which proved clinically ineffective. Synthakyne represents a strategic shift, designing molecules to selectively target the trimeric alpha-beta-gamma receptor found on potent, antigen-activated T cells, avoiding widespread, toxic stimulation.
Contrary to the popular belief that antibody development is a bespoke craft, modern methods enable a reproducible, systematic engineering process. This allows for predictable creation of antibodies with specific properties, such as matching affinity for human and animal targets, a feat once considered a "flight of fancy."
T-cell receptor (TCR) therapies offer a significant advantage over monoclonal antibodies by targeting intracellular proteins. They recognize peptides presented on the cell surface, effectively unlocking 90% of the proteome and requiring far fewer target molecules (5-10 copies vs. 1000+) to kill a cancer cell.
Pathways like integrins have long been of interest but lacked effective therapeutic approaches. The advent of new technologies, such as antibody-drug conjugates and checkpoint inhibitors, has created opportunities to re-explore these older targets with potent, modern drugs, breathing new life into decades-old research.
Dr. Radvanyi emphasizes that foundational discoveries in immunotherapy arose from basic immunology and serendipitous observations, like his own unexpected T-cell proliferation with an anti-CTLA-4 antibody. This highlights the risk of over-prioritizing translational research at the expense of fundamental, curiosity-driven science.
Modern, highly sensitive assays often detect high rates of anti-drug antibodies (ADAs). However, the critical question for drug developers isn't the ADA incidence rate itself, but whether that immune response actually impacts drug exposure, efficacy, or overall patient outcome.
Many innovative drug designs fail because they are difficult to manufacture. LabGenius's ML platform avoids this by simultaneously optimizing for both biological function (e.g., potency) and "developability." This allows them to explore unconventional molecular designs without hitting a production wall later.
A significant, often overlooked, hurdle in drug development is that therapeutic antibodies bind differently to animal targets than human ones. This discrepancy can force excessively high doses in animal studies, leading to toxicity issues and causing promising drugs to fail before ever reaching human trials.
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.