ADC Programs

IKS04

CA242-directed ADC for GI cancers

IKS04 is the first 'ultra-low DAR' ADC in clinical development for solid tumors

Iksuda received FDA IND clearance for IKS04 in July 2026, and Phase 1 preparations are underway (NCT07738939) for assessment in patients with advanced or metastatic GI cancers. The study will take place in investigative sites across the US.

The IKS04 development program has been designed to overcome the challenge of solid tumor penetration for high potency payloads. In a first for the field, the ADC will be co-administered with unconjugated antibody, akin to a dosing regimen that is already used in radioimmunotherapy.

IKS04 represents a new approach for the treatment of GI cancers.

Development status

ADC

IKS04

Target

CA242

Indication

GI tumours

Research Pre-clinical Clinical

Differentiation by design

Iksuda's IKS04 program has been designed to overcome challenges often associated with targeting therapies in solid tumors, recognising the need for;

highly-potent payloads to drive suitable efficacy, especially in colorectal cancers;
payload mechanisms other than tubulin-inhibition (inherent resistance of GI cancers to this mechanism) or topoisomerase-I inhibition (low clinical activity);
antigen targets with relevance across GI cancers and with favorable expression profiles.

IKS04 is comprised of an anti-CA242 antibody, engineered for site-specific conjugation of potent PBD prodrug payloads, DNA-cross-linking being a more relevant mechanism for these highly difficult-to-treat cancers, especially colon adenocarcinomas.

Tumor-selective activation and release is vital for the safe delivery of these payloads

PBD-based ADCs using traditional conjugation chemistries and linker formats are invariably associated with poor toxicity profiles. Like all Iksuda's ADC programs, IKS04 incorporates pro-drug technology with tumor-selective payload release through glucuronide triggers. In pre-clinical testing, IKS04 is associated with the highest therapeutic index for any PBD-containing ADC directed towards solid tumors.

In addition, IKS04 will be administered via an innovative dose regimen - the IKS04 Regimen - with co-administration of unconjugated antibody akin to a dosing regimen used in radioimmunotherapy.

In its design, a beta-glucuronide linker is used for tumor-selective payload release, whilst a second beta-glucuronide moiety improves hydrophilicity and plasma stability of the PBD prodrug.

Payload release and ADC activation requires processing by beta-glucuronidase, an enzyme overexpressed in cancer cell lysosomes, active only at acidic pH and with low expression in normal tissues.

IKS04 – designed to deliver potent anti-cancer activity and raised TI for treatment of GI tumors

Ultra-potent DNA modifying payloads represent an appropriate choice for GI tumors where treatment choices remain poor. Traditional payloads approaches have failed in hard-to-treat cancers; cancers of the colon, rectum, stomach, pancreas, bladder, and uterus require powerful MOA-based payloads for clinical success.

However, such payloads need to be delivered precisely and be associated with a suitable safety & efficacy profile. Iksuda’s ADCs utilize tumor-selective activation and release of payloads through the incorporation of glucuronide linkers and triggers.

Iksuda’s IKS03 and CStone’s ROR1-driected ADC program validated the potential of the PBD prodrug approach in solid and haematological tumors.

Like IKS04, these programs deliver a highly potent, talirine-like PBD through the BG-driven mechanism. In preclinical studies for IKS03, tumor-selective delivery drives class leading efficacy and safety, resulting in significantly enhanced TI over Zynlonta. This ADC design is also associated with bystander effect, suggesting that solid tumors with heterogeneous/ low expression may also benefit.

For our IKS04 program, Iksuda selected CA242 as an appropriate target for GI tumors. It is a tumor-specific isoform of Muc-1 which associated with high expression abundance and high tumor selectivity.

An anti-CA242 (or CanAg) antibody is engineered for site-specific conjugation of a PBD prodrug, where a BG linker is used for tumor-selective payload release, and a second BG moiety improves hydrophilicity and provides added reassurance against unwanted binding to proteins in plasma. β-glucuronide is overexpressed in cancer cell lysosomes, active only at acidic pH and with low expression in normal tissues.

The high expression abundance of CA242, especially in high-expressing models of gastric and colon cancers, results in an antigen barrier which prevents deep penetration into tumor cells. A co-administration approach, where naked antibody is co-administered with ADC, overcomes this hurdle.

In preclinical studies, IKS04 delivers potent and consistent anticancer efficacy across a range of xenograft models of GI cancers. Toxicology studies in monkeys confirm a clinically relevant TI, this TI being higher than any other PBD-associated ADC assessed in solid tumors.

CA242 is a sound target for ADCs directed towards GI cancers

CA242 is a cancer-associated glycotope that is strongly expressed on cells of several solid tumors with limited normal tissue expression.
It is present in the majority of colorectal, gastric, pancreatic and biliary tract cancers, and around half of bladder, endometrial and lung cancers.
CA242 has been clinically validated as a solid tumor target through cantuzumab ravtansine
- This ADC showed clear, but limited, anti-tumor activity and was discontinued after disappointing Phase 2 results
- Limited activity due to poor sensitivity of GI cancers to tubulin inhibitors resulting from spindle checkpoint mutations

The IKS04 Regimen - an ultra-low DAR approach

Due to the high abundance in CanAg-high expressing models – higher than that seen with HER2 – an antigen barrier lowers tumor penetration and ADC efficacy compared with CanAg-low models. CanAg represents a perfect target for a co-administration approach, alongside the unconjugated anti-CA242 antibody.

In preclinical studies, IKS04, administered as a single dose, induces impressive efficacy across a range of CanAg-expressing models and GI tumors – significantly higher than the clinical benchmark ADC cantuzumab ravtansine, (a CanAg-directed ADC which was suspended during clinical trials by Immunogen due to a sub-optimal profile) in all xenografts tested.

However, activity is highest in low-expressing models and lowest in high-expressing models suggesting that high expression abundance impacts tumor penetration.

For this antigen, the high CanAg-expressing Colo205 (colorectal adenocarcinoma) and SNU16 (gastric adenocarcinoma) models, the copies/ cell are ultra-high compared with typical targets, at up to 11.5 million. This is even greater than HER2, though far more tumor-specific.

The addition of unconjugated anti-CanAg antibody to IKS04 significantly reduces MED in high- and very high-expressing models with minimal impact on the efficacy observed for the ADC in low-expressing models.

Importantly, this enhancement in efficacy does not negatively impact toxicity thresholds. In toxicology studies in rats and non-human primates, ultra-low DAR IKS04 is associated with a favorable, clinically desirable TI.

Tackling the challenge of solid tumor penetration for high potency payloads

Ultra-low DAR regimen, through co-administration of ADC with unconjugated antibody, improves ADC distribution within the tumor and increases efficacy

Thurber et al; https://doi.org/10.1158/1535-7163.MCT-25-0484

IKS04: a new approach for hard-to-treat GI cancers

Highly potent proPBD payload with tumor-selective activation

Highly tumor-specific, high density GI cancer target; CA242

Site-specific homogeneous conjugation

Ultra-low DAR to overcome tumor penetration/ payload delivery challenges for high potency payloads

Class leading TI

Phase 1 overview

The Phase 1 trial (NCT07738939) is an open label, uncontrolled non-randomized multi-center, 2 part study assessing IKS04 in patients with CA242-expressing GI cancers that are either relapsed, refractory, or intolerant of existing therapies, or for which no standard of care is available

Part I is a dose escalation 3+3 design study, with a primary objective of safety (MTD)

Part II is a dose expansion study in specified indications, with a primary objective of Objective Response Rate (ORR)

The study is being conducted in investigative sites in the US

Investigative sites:

UCLA Medical Center, California, 90404

Mass General Hospital, Boston, Massachusetts, 02114

Vanderbilt University Medical Center, Nashville, Tennessee, 37232

MD Anderson Cancer Center, Houston, Texas, 77030

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We are delighted to advance our 3rd ADC program to the clinic: IKS04, a CA242-pro-PBD ADC for GI cancers.

The IKS04 Regimen is an innovative dosing approach for an ADC which is employed to overcome the challenge of solid tumor penetration for high-potency payloads.