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Rather than waiting for resistance to one payload and then switching, give two mechanisms from day one, as HIV therapy does.
Rather than waiting for resistance to one payload and then switching, this idea gives two payload mechanisms from day one, as HIV therapy does. A TOP1 plus tubulin or TOP1 plus DNA-crosslinker dual-payload TROP2 or HER2 ADC is expected to outperform a single-payload ADC in first-line metastatic breast cancer at equivalent toxicity, because combination therapy prevents selection of resistant clones and dual-payload ADCs achieve this without doubling antibody dose. ACR335 and the Sutro and Mersana programmes show manufacturability. The test is phase 1 dose-finding then a randomised phase 2 against a single-payload ADC. Speculative in maturity, it addresses the bottlenecks Acquired resistance to every therapy and Too many combinations to test.
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This review is the conceptual basis for trastuzumab, pertuzumab, HER2 antibody-drug conjugates and EGFR inhibitors, and for the HER3-mediated resistance that later drugs try to overcome.
Shares Yarden and Sliwkowski 2001: untangling the ErbB signalling network, Payload-class switching as the rule for ADC sequencing, TROP2, HER2.
Shares Yarden and Sliwkowski 2001: untangling the ErbB signalling network, Payload-class switching as the rule for ADC sequencing, TROP2, Acquired resistance to every therapy.
Shares Dual-payload ADC, Site-specific conjugation & linker chemistry, Acquired resistance to every therapy, Antibody-drug conjugate (ADC).
Shares Payload-class switching as the rule for ADC sequencing, Too many combinations to test, Acquired resistance to every therapy, Antibody-drug conjugate (ADC).
Shares Payload-class switching as the rule for ADC sequencing, Too many combinations to test, Acquired resistance to every therapy, Antibody-drug conjugate (ADC).
Shares Yarden and Sliwkowski 2001: untangling the ErbB signalling network, TROP2, HER2, Antibody-drug conjugate (ADC).
Shares Payload-class switching as the rule for ADC sequencing, Acquired resistance to every therapy, Antibody-drug conjugate (ADC).
Shares Yarden and Sliwkowski 2001: untangling the ErbB signalling network, HER2, Triple-negative breast cancer (TNBC).