ADC Design Strategy
Iksuda's goal is to design & deliver better ADCs which address unmet clinical needs
We design our ADCs to meet our criteria for clinically meaningful differentiation over on-market comparators or standard of care through enhanced TI and wider clinical utility. We want to advance new therapies for cancers of high unmet need.
A toolbox of ADC assets is critical to design optimal ADCs for any given target. We believe that optimal ADCs cannot be achieved through a single platform approach, and we have built a suite of ADC assets through in-house and collaborative research. Our assets cover the entire spectrum of ADC design.
Iksuda's ADC toolbox
A multi-platform approach is fundamental to the design of optimal ADCs for any given target
All our ADCs benefit from tumor-selective payload activation and release for added safety, delivered today via beta-glucuronide linkers. This approach is now clinically validated in our IKS014 ADC program.
We continue to optimize linker-payload formats for intra-tumoral delivery, whilst expanding our payload options to ensure coverage of all known ADC classes and to introduce powerful new mechanisms.
Iksuda’s protein alkylating payload, ProAlk, is a world’s first and enables the expansion of novel ADCs and a pathway to help overcome ADC sequencing issues. It has been designed to meet specific characteristics in payload design which enable wide clinical applicability.
| Binders | Fit for purpose, with optimal ADC characteristics Sourced through proprietary discovery, engineering enhancement or in-license |
| Bioconjugation | Stable conjugation for wild type or site-specific antibodies - LCBs ConjuAll is used in Iksuda's clinical-stage programs and IKS04. - Iksuda's proprietary PermaLink is used in all other in-house ADC programs. |
| Linkers | Highly advanced tumor-selective cleavable linker formats - A major area of innovation at Iksuda, building on past formats to drive increased utility and expanded application- Initial focus on glucuronide-based formats, with research into next generation variants and 'beyond glucuronide' approaches- The 'Glu-linker' format approach is now clinically validated through our IKS014 program |
| Payloads | Expanding portfolio of advanced novel ADC payloads - DNA cross-linker prodrugs - incorporated in IKS03 & IKS04 - Protein alkylator prodrug payloads (Iksuda's proprietary ProAlk class)- CDK 11s: novel pro-apoptotic kinase inhibitors - specialty payloads for selected tumor types- Topoisomerase II inhibitor prodrug payload - Novel DNA-modifying approaches in early development |
Making informed decisions in ADC design
ADC design expertise, coupled with an ability to learn from past experiences, is required to understand the nuances of the modality for maximal probability of success
We strive to improve and enhance all platforms to deliver a relevant payload MOA for the tumor and target safely and selectively to the cancer cell to drive maximum impact.
Payload MOA defines an ADCs toxicity profile, is fundamental to anti-cancer activity and is critical in ADC sequencing. It is important to select the right MOA and potency for the targeted tumor, balancing this against a target's expression profile.
Similarly, target antigen choices determine toxicity risk, and offer insight towards payload MOA and cytotoxic potency. Of course, they also determine the indication range of the associated ADC.
Relevant clinical indications define potential payload MOA options for testing, the clinical development strategy and selection of relevant benchmarks.
Experienced-based ADC design for clinically meaningful differentiation
Every ADC needs careful & individual design consideration to achieve its optimal profile: a ‘single platform approach’ is inappropriate
The modular nature of the ADC modality provides unparalleled opportunity for continued technologic improvement for next wave ADCs. It is important to learn from past experiences, to understand reasons for failure and success, to be able to improve upon ADC design for onward success.
IKSUDA avoids dogma to drive innovation: we design class leading ADCs with tailored components for maximum impact. All our ADCs contain glucuronide-driven payload activation for added precision and safety.
ADCs are evaluated for differentiation over benchmarks and ADC design is then honed before identifying development candidates. Iksuda’s decision to move any ADC program into IND enabling studies is based on whether we see clinically meaningful improvement in TI over relevant in-clinic and on-market comparators. Our evaluations include efficacy studies against comparators across a range of mouse xenografts and PDX models, as well as pilot toxicology in non-human primates.
The later stage pipeline provides validation for the tumor-selective linker and triggers used in earlier ADC programs. Iksuda is leveraging this validation to build ADCs against novel targets in the ADC space. Here, we select targets according to potential utility across tumor indications of high unmet need and compare profiles with current standard of care in relevant preclinical When designing its ADCs, Iksuda evaluates the best technology available for each ADC component, testing and honing the construct to achieve an optimal profile.
If the lead candidate achieves or exceeds our benchmark TI, established to ensure clinical meaningful differentiation vs in-clinic or on-market comparators, we progress through IND enabling studies. In making our decisions, we avoid reliance on dogmatic assumptions and integrate existing data on clinical success and preclinical studies.
Enhancing probability of success
Iksuda’s pipeline prioritization is based on the vital triad for ADC success, with probability of success being defined by the relationship of this triad:
- Payload MOA;
- Target properties;
- Relevant clinical indications
New technology validation is conducted through comparative clinical benchmark studies to define differentiation index. After identification of suitable clinical benchmarks with evidence of on-target clinical activity, our team decides whether to explore the same target for the same indication.
We then compare new technology options designed to overcome the identified limitations of the selected clinical benchmarks in representative preclinical models.
For each program, we establish criteria for design success, including:
- Does the ADC need to be more powerful?
- Do we need to demonstrate an improved toxicity profile?
- Should we ensure broader utility through a wider clinical indication profile?
Iksuda only progresses ADC programs which meet our design criteria into active development. We apply validated new technologies to novel targets for improved probability of clinical success, drawing on validation of the technology from comparative analysis with known targets.
When considering new technologies, Iksuda again works to defined criteria. For example, for payload related decisions, we assess whether:
- A novel payload MoA will drive differentiated sensitivity/resistance profiles.
- Improved selectivity for activation & release improves efficacy and/ or decreases toxicity.
- Decreased off-target effects for improved on-target dependence.
- Enhanced potency increases sensitivity or power.
- Improved biophysical properties improves ADC design flexibility.
Iksuda continually explores new, enhanced innovation programs, investing in next generation efforts for enhanced differentiation in a continuous effort to drive best-in-class technologies.
Contact us about partnerships for ADC design & development
Ian Evetts
