Author:Bio-four
Introduction
On March 26, 2025, the TROP2 dual payload ADC drug KH815 developed by Kanghong Biotech received clinical trial approval from the Australian HREC and obtained clinical approval in China on April 16, 2025, making it the world’s first dual payload ADC approved for clinical use.
During this year’s AACR conference and related patents made public, a considerable amount of preclinical data has been disclosed, and the recent issue of Molecular Cancer Therapeutics further published the preclinical technical details of KH815.
TROP2 Dual Payload ADC
The TROP2 dual payload ADC drug KH815 delivers two cytotoxic agents with different mechanisms: Exatecan (EXA), a topoisomerase I inhibitor that disrupts DNA replication, and Triptolide (TPL), an RNA polymerase II inhibitor that suppresses gene transcription, downregulating drug resistance-related proteins such as HSP70 and P-gp, thereby enhancing antitumor effects and overcoming resistance.
Specifically, the Exatecan toxin is linked via VA and PEGylated, using a Michael addition with cysteine for conjugation, MC-PEG2-VA-PAB-Exatecan. The Triptolide is linked via GGFG, also PEGylated, and conjugated using a DBCO click chemistry method based on glycosylation, DBCO-PEG4-GGFG-Triptolide, with DAR values of DAR4 and DAR3.5 respectively.
Mechanistically, the two drugs target DNA and RNA respectively, forming a dual attack to overcome single-agent resistance. TPL is released first, inhibiting HSP70 and P-gp expression, enhancing tumor cell sensitivity to EXA. EXA is then released, continuously killing tumor cells.
In vitro, in various tumor cell lines (such as NCI-H292, NUGC-4, HCT-15), hRS7-E+T demonstrated superior cytotoxic effects compared to single payload ADCs (such as Dato-DXd), effectively inhibiting TOP1 and POLR2A expression, reducing HSP70 and ABCB1 drug resistance gene expression.
In CDX models, in TROP2 high expression, low expression, and resistant models, hRS7-E+T exhibited stronger tumor suppression effects.
In PDX models, in lung cancer, colorectal cancer, and breast cancer PDX models, hRS7-E+T showed more durable antitumor responses.
In resistant models, in Dato-DXd or Trodelvy resistant models, hRS7-E+T still achieved significant tumor shrinkage.
In non-GLP toxicity studies (in crab-eating macaques), the highest non-severe toxicity dose (HNSTD) was 50 mg/kg, with adverse effects primarily being reversible skin reactions (hair loss, pigmentation) and mild blood/liver function changes, with no significant immunotoxicity or bone marrow suppression.KH815 is the first to combine EXA and TPL into an ADC, achieving sequential release and synergistic killing, with the potential to effectively overcome tumor resistance to TOP1 inhibitors, applicable to tumors with varying levels of TROP2 expression, demonstrating good safety and further clinical development value. This provides a new strategy for ADC drug development, expected to address the current limitations of single payload ADC efficacy and resistance issues.
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References:1.A Novel Dual-Payload ADC Platform Integrating Exatecan and Triptolide to Enhance Antitumor Efficacy and Overcome Resistance2.WO2025103474
Further Reading
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