Byung-June Park on triple-payload ADCs and dual-function TCE-ADCs: Breakthroughs in AACR 2025 abstracts
Byung-June Park, Founder of OncoPark, shared a post on X:
“A truly crazy ADC molecule!
AACR 25 Abstract #7334 – Araris’ Nectin-4 targeting triple-payload ADC
This ADC incorporates MMAE and two distinct topoisomerase I inhibitors into a single molecule (DAR 2+2+2). Based on Araris’ previous work, it is likely that the two TOP1i payloads were selected to differ in their bystander effect profiles.
Interestingly, while combining single-payload ADCs at the same dose showed no response, the triple-payload ADC alone induced durable tumor regression. It demonstrated potent activity in high Nectin-4 expression models and low-expression settings, supported by linker stability, prolonged circulation, and high tolerability.
AACR 25 Abstract #7322 – Leads Biolabs’ DLL3 targeting TCE-ADC (LBL-058)
This construct integrates CD3-based T cell redirection with Topo1 inhibitor delivery in a single molecule.
The CD3 binding affinity is intentionally reduced, and the design enables DLL3-mediated targeting followed by internalization and payload release. In this dual-function format, balancing DLL3 and CD3 binding kinetics—while supporting immune synapse formation as a T cell engager and enabling internalization as an ADC—is critical.
If internalization occurs too quickly, the immune synapse may not be maintained long enough for effective T cell-mediated cytotoxicity. Therefore, it may be worth considering designs where payload release can occur independently of internalization.”
Authors: Sun Jianming et al.
Authors: Isabella Attinger-Toller et al.
Paolo Tarantino, Clinical Research Fellow at the Dana-Farber Cancer Institute, shared a post by Byung-June Park on X, adding:
“Who’s ready for triple payload ADCs?!”
Raffaele Colombo, Associate Director of Medicinal Chemistry at Zymeworks, shared a post by Paolo Tarantino on X, adding:
“In this pre-print, they describe multi-payload ADCs with 2, 3, 4, and even 6 different payloads!
TOP1 + PARP1/2 + ATR + CDK4/6 + PI3K + ER…. ADC?”
Antibody-mediated co-delivery of programmable drug combinations
Authors: Xun Meng et al.
Learn more about ADCs in cancer on OncoDaily.
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