The future of advanced prostate cancer treatment may involve combining ADCs with bispecific T-cell engagers. This strategy could use ADCs for a short duration to deliver a potent hit, followed by immunotherapy to achieve durable remission, potentially reducing toxicity and enabling earlier use.

Trastuzumab deruxtecan (TDXD) and datopotamab deruxtecan (Dato-DXd) share the same cytotoxic payload, yet Dato-DXd has a much lower rate of interstitial lung disease (ILD). This indicates the toxicity is driven by the antibody-antigen interaction, not the payload itself.

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.

Next-generation bispecific antibodies are engineered with a silenced Fc portion. This design feature intentionally limits the molecule's circulation time, allowing it to clear rapidly. This helps manage toxicity if it occurs and prevents overstimulation of the immune system via Fc gamma receptors, improving the safety profile.

Combining two payloads in an Antibody-Drug Conjugate (ADC) introduces a major risk: new, synergistic toxicities not seen with either agent alone. This complicates dose-finding and safety assessment, requiring developers to anticipate and monitor for entirely novel side effects.

The primary reason Antibody-Drug Conjugates (ADCs) stop working is payload resistance, a shift from the traditional belief that failure stems from tumors losing the target antigen. This insight drives development of multi-payload ADCs to overcome this resistance mechanism.

Accession's second product is a bispecific antibody that binds to all cancer cells. While this would be dangerously toxic if delivered systemically, their targeted virus delivery system ensures it is only produced inside the tumor. This strategy makes previously "undruggable" therapeutic concepts viable.

Unlike older antibody-drug conjugates (ADCs), newer agents are designed so their chemotherapy payload can diffuse out of the target cell and kill nearby tumor cells that may not even express the target antigen. This "bystander effect" significantly enhances their anti-tumor activity.

As multiple effective Antibody-Drug Conjugates (ADCs) become available, the primary clinical challenge is no longer *if* they work, but *how* to use them best. Key unanswered questions involve optimal sequencing, dosing for treatment versus maintenance, and overall length of therapy, mirroring issues already seen in breast cancer.