Breakthrough drugs aren't always driven by novel biological targets. Major successes like Humira or GLP-1s often succeeded through a superior modality (a humanized antibody) or a contrarian bet on a market (obesity). This shows that business and technical execution can be more critical than being the first to discover a biological mechanism.

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.

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.

Abivax's drug has a novel, not fully understood mechanism (miR-124). However, analysts believe strong clinical data across thousands of patients can trump this ambiguity for doctors and regulators, citing historical precedents like Revlimid for drugs that gained approval despite unclear biological pathways.

Protagonist believes its oral IL-23 blocker will not just compete with existing injectables but will capture a new market. They target the over 50% of eligible patients who currently take no therapy due to a dislike of injections or the safety profiles of other oral options, thereby expanding the total addressable market.

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.

The failure of the TROPiCS-04 trial for sacituzumab govitecan may not indicate the TROP2 ADC class is ineffective. Experts suggest problems with dosing and toxicity management (e.g., neutropenia) during the trial could be the real culprit, arguing that the drug class still holds promise.

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.