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When a released payload leaks out of the targeted cell and kills its neighbours, including cells that lack the target.
In an antibody-drug conjugate, the bystander effect is what happens when the released payload leaks out of the targeted cell and kills neighbouring cells, including cells that lack the target. It requires a cleavable linker and a membrane-permeable payload such as DXd, MMAE or SN-38. This explains why Trastuzumab deruxtecan works in HER2-low tumours while T-DM1, whose payload is not permeable, does not, and the same leakage is a source of toxicity to adjacent normal tissue. The concept is linked to the Antibody-drug conjugate (ADC) and Topoisomerase-I inhibitors technologies and to the payload terms DXd, MMAE and MMAF, and readers also meet it in the Sacituzumab govitecan and Polatuzumab vedotin entries and the DESTINY-Breast03 and DESTINY-Breast04 papers.
Ball-and-stick model from PubChem 2D record (no 3D conformer available). PubChem record
Showing the molecule this term concerns: Trastuzumab deruxtecan.
For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.
Patients whose breast cancer was previously called HER2-negative may now be eligible for an effective HER2-directed drug if their tumour has even low-level HER2 staining, so pathology reports must now distinguish HER2-low (1+ or 2+/ISH-negative) from HER2-zero. This applies to metastatic disease after at least one line of chemotherapy; it does not mean these patients benefit from trastuzumab or other older HER2 drugs.
One term page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
Shares MMAF, DM1, DM4, Tumour-on-a-chip with blood flow to test whether big drugs actually get in.
Shares CL2A, Topoisomerase-I inhibitor payloads, Drug efflux pumps (ABC transporters), Sacituzumab govitecan.
Shares DXd, MMAE, Tubulin inhibitor payloads, Topoisomerase-I inhibitor payloads.
Shares mc-Val-Cit-PABC, MMAE, Tubulin inhibitor payloads, Antibody-drug conjugate (ADC).
Shares DXd, Topoisomerase-I inhibitor payloads, Sacituzumab govitecan, Trastuzumab deruxtecan.
Shares mc-Val-Cit-PABC, MMAE, Tubulin inhibitor payloads, Antibody-drug conjugate (ADC).
Shares Topoisomerase-I inhibitor payloads, Drug efflux pumps (ABC transporters), Topoisomerase-I inhibitors (and ADC payloads), Antibody-drug conjugate (ADC).
Shares DM1, DM4, MMAE, Tubulin inhibitor payloads.