ProAlk
Introducing a new payload mechanism
A novel duocarmycin derivative, ProAlk exerts its cell killing impact through the alkylation of cystolic proteins.
Whereas traditional DNA alkylators localize in the nucleus of cancer cells, ProAlk is localized in cytosols.
ProAlk shows potent activity across a wide array of tumor cell lines supporting use in multiple indications.
Iksuda’s design incorporates glucuronide triggers for release and activation of the free drug: the prodrug is 105 less active than the free drug. The glucuronide linker utilizes novel linker chemistry for release of hydroxyl-based payloads.
ProAlk has been designed for ADC relevance
In preclinical proof-of-concept testing, ProAlk has been shown to be MDR-resistant, exhibit potent bystander activity and induce immunogenic cell death.
ProAlk-containing ADCs show excellent stability via the use of Iksuda’s proprietary bioconjugation chemistry, PermaLink, and potent in vivo efficacy at dose levels which are expected to drive good tumor penetration.
ADC pilot toxicology assessments in NHPs have demonstrated excellent tolerability at doses far in excess of MEDs in mouse xenografts.
ADC sequencing will be the major development challenge in the future
Why are payloads with new MOAs needed?
ADCs initiating today using tubulin or topoisomerase I inhibitors may be irrelevant when they reach clinic in 3-5 years.
Today there are >700 ADCs already in clinical and preclinical development with tubulin or topoisomerase I inhibitor payloads. There are almost 50 trials topoisomerase I inhibitor ADCs in Phase 3 and > 80% of the 83 ADCs which entered the clinic in 2024 use this payload mechanism.
In the coming 3 – 5 years, there will be multiple ADCs with tubulin or topoisomerase I inhibitors in most indications.
ADC sequencing will be the major development challenge in the future
Current clinical data shows poor performance when ADCs are sequenced with the same payload MOA, independent of target, and good performance with alternative MOAs, independent of target.
The clinical development path for new ADCs containing tubulin or topoisomerase I inhibitor payloads will be challenging. Most patients in clinical trials will already have been exposed to these payloads previously.
Differentiation from tubulin and topoisomerase I inhibitor payloads will become imperative.
There is a high risk of irrelevancy with current ADC technologies. Differentiation from tubulin and topoisomerase I inhibitor payloads will become imperative in the near future
Proprietary ProAlk prodrug linker payload format provides high tumor selectivity
Iksuda has developed linkable ProAlk prodrug variants with tolerability-enhancing glucuronide triggers, alongside PermaLink bioconjugation for highly stable ADCs. The linker incorporates novel self-immolative chemistry for release of hydroxyl-based payloads.
The prodrug form requires cleavage by lysosomal glucuronidase for release and activation, this enzyme being upregulated in many cancer cells.
Iksuda is building a pipeline of ProAlk ADCs
Based on ProAlk sensitivity analysis, we are progressing multiple ADC programs to known and novel targets for hard-to-treat cancers.
We are focused on developing a new class of ADCs for the potential treatment of cancers such as lung, colon, stomach, esophagus, head & neck, kidney, breast (TNBC) and multiple myeloma.
We are also seeking collaboration/ license partners for the advancement of ProAlk-containing ADCs.
Continued innovation into payloads and payload delivery
Expanding portfolio of advanced payload options
Iksuda continues to research and develop new payload series, using our prodrug approach for next generation ADCs.
We recognise the need for access to a variety of payload mechanisms since optimal ADC design is founded on matching the most appropriate payload MOA to the targeted antigen and relevant tumor indication(s).
Our research programs include a CDK11 series, where we are working in collaboration with Cancer Research Horizons to advance a novel pro-apoptotic TKI series for selected tumor sub-types. The combination of these relatively potent TKIs with tailored tumor-selective cleavable linker formats and high DAR technologies offers a potentially new approach in ADC design.
Beyond this series, we are also researching DNA monoalkylator and topoisomerase II inhibitor payloads. Our ADC design principles include matching the most relevant payload MOA with the target and its associated tumor(s) for optimal efficacy, delivered via tumor-selective linker formats for added safety. We are researching ways tailor payload release and activation kinetics according to MOA, thus optimizing intra-tumoral delivery.
Iksuda is building a rich suite of novel payloads
Iksuda's prodrug payload options should enable high ADC power with good TI
Iksuda's premise is to optimize the delivery of each payload MOA through tailored release & activation kinetics. We believe that we can extend the utility and power of our ADCs over traditional approaches, whilst simultaneously enhancing TI
Iksuda technologies enable better performing ADCs.
Our ADC design principles include matching the most relevant payload MOA with the target and its associated tumor(s). We are focused on optimizing the release and activation of payload candidates according to MOA, thus optimizing intra-tumoral delivery.
We continue to build our series of proprietary payload options for known and novel mechanisms. For some ADC programs, we have noted that our design elements bring traditional payloads back into play and/ or extend their clinical applications, enabling more options.
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