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.
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Instead of waiting for allergy patients to have symptoms on study days, Dr. Abelson’s team created a model to induce the allergic reaction in a controlled way. This 'Conjunctival Allergy Challenge' allowed for precise, predictable testing of new drugs, dramatically speeding up development.
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.
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.
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.
The current boom in immunology and autoimmune (I&I) therapeutics is not a separate phenomenon but a direct consequence of capital and knowledge from immuno-oncology. Many of the same biological pathways are being targeted, simply modulated down (for autoimmune) instead of up (for cancer), allowing for rapid therapeutic advancement and platform reuse.
Despite AI's power, 90% of drugs fail in clinical trials. John Jumper argues the bottleneck isn't finding molecules that target proteins, but our fundamental lack of understanding of disease causality, like with Alzheimer's, which is a biology problem, not a technology one.
To combat immunosuppressive "cold" tumors, new trispecific antibodies are emerging. Unlike standard T-cell engagers that only provide the primary CD3 activation signal, these drugs also deliver the crucial co-stimulatory signal (e.g., via CD28), ensuring full T-cell activation in microenvironments where this second signal is naturally absent.
The excitement around ICOS agonists for activating effector T-cells ignored a critical biological nuance: ICOS is also highly expressed on suppressive T-regulatory cells. Dr. Radvanyi notes this oversight led to therapies that inadvertently activated the very cells they aimed to overcome, a cautionary tale on scientific dogma.
While the field focuses heavily on T-cells and myeloid-derived suppressor cells, Dr. Radvanyi argues that dendritic cells have not received enough attention. Better understanding how to activate these primary antigen-presenting cells is crucial for priming effective and durable anti-tumor immune responses, especially within tertiary lymphoid structures.
Bi-specific T-cell engagers (BiTEs) are highly immunogenic because the mechanism activating T-cells to kill cancer also primes them to mount an immune response against the drug itself. This 'collateral effect' is an inherent design challenge for this drug class.
