Tumour-selective Payload Activation
All Iksuda’s ADCs benefit from tumor-selective activation and release of payload for added safety.
Iksuda's prodrug approach is driven by the use of β-glucuronide (BG) linkers and triggers, ensuring that the payload is only released in cancer cells, thus avoiding the risk of on-target, off-site toxicity.
β-glucuronidase is overexpressed in many cancers and is isolated to cancer cell lysosomes. It is active at acidic pH, has low expression in healthy tissues and is not found in circulation. Traceless chemistry allows use of BG linker/ triggers with multiple payload classes.
In our ADC pipeline, BG linkers are used with MMAF, PBDs and our new payload class of protein alkylators, ‘ProAlk’.
The BG-driven prodrug approach is now clinically validated
Through ongoing clinical studies of IKS014 (as FS-1502 in China), and CStone’s ROR1-directed ADC, CS5001, the BG linker approach has been shown to drive enhanced TI, with potent activity allayed to favorable tolerability profiles compared with competitor programs.
In Phase 1 and Phase 2 studies, FS-1502 shows potent anti-cancer activity in heavily pre-treated patients with HER2+ solid tumors, including those of the breast and stomach. This potency is also associated with an improved safety profile over other HER2-directed therapies: it is not associated with dose-limiting respiratory toxicities, neutropenia or ocular toxicity and there is a notable absence in other events frequently seen in HER2-targeting therapies such as nausea, vomiting and severe fatigue.
CS5001 is associated with a higher objective response rate (ORR) as a monotherapy for both aggressive and indolent advanced lymphomas compared with competitors.
Tumor-selective activation & release of the right payload drives a differentiated clinical profile
The selection of a tubulin binder MoA for breast cancer is a logical choice, and MMAF allows potential benefits in ADC sequencing, including after post-Enhertu failure. However, MMAF-based ADCs such as Blenrep are associated with dose limiting ocular toxicity and few MMAF-ADCs are currently in clinical study.
Compared with Blenrep, IKS014 (FS-1502 in China) shows a marked reduction in dose-related ocular toxicities and an absence of those associated with the cornea, demonstrating strong validation of the benefit of tumor-selective activation. There is also distinct difference in pulmonary toxicities and neutropenia compared with Enhertu, as well as a marked reduction in thrombocytopenia compared with Kadcyla.
Data presented at SABCS 2023: data cut-off December 2022 after a median follow up of 5.2 months.
Tumor-selective payload release for enhanced precision targeting
The BG linker/ trigger format leads to superior efficacy and wider tolerability than clinical benchmarks
For example, Iksuda’s CD19-directed ADC IKS03 demonstrates an order of magnitude improved differential in tumor vs normal cell killing compared with the clinical benchmark SGN19B.
SGN19B induces total B-cell depletion at doses below its effective dose whereas IKS03 does not induce complete B-cell depletion at doses far in excess of its effective dose. This supports the hypothesis of differentiated tumor cell activation of linker/ payload due to the difference in glucuronidase activity. 
Expanding clinical utility of tumor-selective payload activation
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