IKS04: Iksuda’s novel CA242-directed ADC for GI tumors

A new ADC with a favorable therapeutic window:

CA242, the target for IKS04, is highly expressed in colorectal, pancreatic, and gastric cancers, while its expression in normal tissues is limited. Previous clinical studies have demonstrated its potential as a druggable ADC target, as well as the limitations of microtubule inhibitor-based payloads in gastric tumors. IKS04, which employs a potent DNA-damaging payload, drives significant improvement in anti-cancer activity across a range of in vivo xenografts and a good therapeutic index.

Novel dosing regimen:

CA242 has inordinately high expression abundance in high-expressing colon and gastric models, resulting in an antigen barrier which precludes tumor penetration of the ADC. Leveraging an ‘ultra-low DAR approach through co-administration of naked antibody with the ADC, IKSUDA has demonstrated an enhancement in tumor penetration, enabling consistently low minimally effective doses across all CA242-expression models. The therapeutic index of IKS04 is significantly higher than all PBD-based ADC programs so far assessed use in for solid tumors.

IKSUDA plans to initiate clinical trials of IKS04 using the ultra-low DAR dosage regimen in the near future.

Poster session details:

2885. IKS04, an antibody drug conjugate with a highly potent DNA crosslinker payload for the treatment of gastrointestinal cancers 

Session Category: Experimental and Molecular Therapeutics

Session Title: Antibody-Based Cancer Therapeutics 2

Session: Monday 4/28/2025 2 - 5 PM

Location: Poster Section 15

Poster Board Number: 24

Introducing ProAlk – the world’s first protein alkylating ADC payload

Iksuda’s ProAlk is a novel seco-CBI-based prodrug payload which primarily exerts cell-killing activity through the alkylation of cytosolic proteins. It is used in ADC formats alongside tumor-selective glucuronide triggers that attenuate the potency of the payload until uptake into target cancer cells and selective release in the lysosome. The glucuronide, combined with Iksuda’s proprietary PermaLink conjugation chemistry, ensures ADC stability.

Iksuda has demonstrated preclinical proof of concept for this new payload in ADC formats. ProAlk-containing ADCs demonstrate excellent profiles: studies have demonstrated strong in vitro potency and an unprecedented level of bystander activity; MDR resistance; induction of immunogenic cell death for potential activation of anti-tumor immunity; durable tumor regressions in xenograft models; excellent tolerability in monkeys.

The free payload is highly active against a broad array of cancer cell lines representing a variety of solid tumors suggesting that ProAlk is a promising candidate for the development of ADCs with a novel MOA for the treatment of solid tumors. The combination of ProAlk and tumor-selective activation technology enables powerful and highly selective ADCs for potential best-in-class therapies. In addition, payload novelty supports ADC sequencing with tubulin and/ or topoisomerase I inhibitor containing ADCs.

Iksuda is currently building a pipeline of ProAlk-ADCs.

Poster session details:

1579. PA289, a prodrug linker-payload with a novel mechanism of action for the development of antibody drug conjugates 

Session Category: Experimental and Molecular Therapeutics

Session Title: Antibody-Based Cancer Therapeutics 1 Session: 4/28/2025 9 AM - 12PM Location: Poster Section 15 Poster Board Number: 28

PermaLink®, a stable and scalable bioconjugation platform as an alternative to maleimide-based conjugation

PermaLink (PL) comprises simple, stable, and adaptable conjugation chemistry that overcomes the instabilities associated with the retro-Michael exchange of traditional maleimide-based chemistry. This platform enables ADC generation with a range of drug-to-antibody ratios (DAR) and can be applied to multiple payloads and linker chemistries to improve conjugate properties and maximize the therapeutic index of ADC therapeutics.

PL-based conjugates are associated with excellent stability in murine and human plasma. In proof-of-concept models, PL-Glu-ADCs induced potent tumor regression in xenograft models and were very well tolerated in cynomolgus monkeys, showing improved tolerability over MMAE-based ADCs with maleimide-cathepsin B cleavable linkers. In addition, PL-glu-MMAE conjugate were associated with favorable PK profile in monkeys with high stability in circulation consistent with improved bioconjugation.

PL offers a simple, stable alternative to maleimide-based ADC bioconjugation moieties and confers a favorable preclinical anti-tumor activity and safety profile.

Iksuda is building a pipeline of best- and first-in-class ADCs comprised of PL and glucuronide-driven tumor-selective activation of its novel ProAlk payload.

Poster session details:

1570. PermaLink®, a stable and scalable bioconjugation platform as an alternative to maleimide-based conjugation 

Session Category: Experimental and Molecular Therapeutics

Session Title: Antibody-Based Cancer Therapeutics 1

Session: Monday 4/28/2025 9 AM - 12 PM

Location: Poster Section 15

Poster Board Number: 19