The development of next-generation ADC drugs has gradually shifted towards the development of new toxins and linkers as foundational technologies. Multi-antibody or multi-toxin approaches have become a new trend. Following Araris and Puzhong’s advancements in tri-toxin and hexatozin,Aarvik has now introduced quadruple antibody-drug conjugates (ADCs).
Aarvik may not have a prominent reputation in the ADC field, but previously published reviews on ADCs have garnered widespread attention. In 2021,Arrivent collaborated withAarvik to develop ADC drugs, and recently,Aarvik announced its patent for quadruple ADCs (WO2025122988).
Aarvik’s ADC construction is noteworthy, utilizing VC-MMAE platform technology, with HC-A118C and LC-V205C mutations for precise coupling. The first development was a HER2 dual-antibody ADC, designed with nanobodies in a tandem format, including attempts at dual-epitope quadruple ADCs.
It also includes a CD30-PD-L1 tri-antibody ADC, similarly designed with nanobodies in a tandem format, utilizing four platforms to construct dual antibodies targeting different PD-L1 epitopes. Coupling was achieved using THIOMAB technology for DAR4 construction, with in vitro activity demonstrating synergy.
Additionally, a Her2/Trop2 tri-specific antibody was constructed, also utilizing THIOMAB technology for DAR4 construction, which showed sustained enhanced cellular potency compared to Her2 mono-specific ADCs.
A Muc16/NaPi2b dual-specificity tetravalent antibody ADC was also designed, which exhibited higher potency in cell mixtures with constant NaPi-2b levels and variable Muc16 expression compared to the monovalent ADCs AB301-ADC (NaPi-2b) and AB302-ADC (MUC-16).
Furthermore, a Her2/Her2/PD-L1 dual-specificity tetravalent antibody ADC was developed, which demonstrates superior efficacy compared to monovalent ADCs.
Additionally, a Her2/Her2/Trop2 tri-specificity tetravalent antibody ADC was also developed, utilizing four different platform technologies to construct the dual-antibody structure, which showed better in vitro cellular efficacy in JIMT1 and SKOV3 cells.
The development of multi-antibody ADCs is currently a hot topic, encompassing two levels of biological mechanisms. On one hand, dual-epitope antibodies enhance ADC endocytosis while also increasing ADC selectivity. On the other hand, the selection of synergistic targets, such as EGFR/HER3, EGFR/c-Met, and HER3/c-Met, has been explored in combinatorial attempts. There are also attempts at target combinations with co-expressed targets like TROP2/Nectin-4, but the expression levels of both targets may introduce new toxicity. The development of multi-antibody ADCs clearly presents more challenges. Disclaimer: The information in this WeChat article is for general reference only and should not be directly used as decision-making content. Bio Frontiers does not assume any responsibility for any losses incurred by any party due to the use of this article’s content. If there are any objections, please contact the editor for modifications.