Promatix Biosciences PBS293: Preclinical Data Show Dual-Target ADC Outperforms Cetuximab Conjugate in Colorectal Cancer Models

UK-based Promatix Biosciences announced preclinical data for PBS293-MMAE, a first-in-class cis-bispecific antibody-drug conjugate targeting both EGFR and EphA2, in models of advanced colorectal cancer. The data, presented at the World ADC London Summit 2026, showed the EGFR EphA2 antibody drug conjugate was more than 50-fold more potent than a cetuximab-based comparator ADC in KRAS-mutant colorectal cancer cells and achieved superior tumour suppression in xenograft studies. The results position Promatix Biosciences PBS293 as a potential entrant into the increasingly competitive ADC landscape in gastrointestinal oncology, where conventional EGFR-targeted therapies remain effective in only a narrow subset of patients.

Trial specifics

PBS293-MMAE is a full IgG1 cis-bispecific antibody–drug conjugate carrying an MMAE (monomethyl auristatin E) cytotoxic payload. The molecule was evaluated in a series of preclinical studies rather than a registered clinical trial. In vitro, the bispecific ADC colorectal cancer programme assessed cytotoxicity in HCT116 cells, a KRAS-mutant human colorectal cancer cell line that is inherently resistant to cetuximab monotherapy in the clinical setting. PBS293-MMAE demonstrated low-nanomolar potency in this cell line, with a greater than 50-fold increase in potency relative to cetuximab-MMAE, a monospecific EGFR-targeted ADC carrying the same payload. In vivo, xenograft studies using the HCT116 cell line showed PBS293-MMAE achieved dose-dependent tumour growth inhibition that was described as significantly higher than that observed with cetuximab-MMAE, along with sustained tumour suppression over the study period. The company did not disclose specific IC₅₀ values, tumour volume measurements, animal numbers, dosing schedules, or formal statistical analyses in the press release, though the full dataset was presented in a poster titled "Hybrid Avidity–Gated EGFR/EphA2 Bispecific ADC Enables Tumour Selectivity and Keratinocyte Sparing," which the company said is available on its website.

A separate set of experiments assessed safety-relevant endpoints. PBS293-MMAE demonstrated substantially lower cytotoxicity in normal human keratinocytes compared to cetuximab-MMAE. This finding is relevant because EGFR is widely expressed in skin, and dermatologic toxicity — including acneiform rash and paronychia — is a well-documented dose-limiting class effect of EGFR-targeted agents. Proteomic analysis combined with fluorescence-activated cell sorting on patient-derived colon cancer xenograft tissue confirmed high levels of membrane co-localisation of EGFR and EphA2, supporting the biological premise that dual-antigen engagement can differentiate tumour from healthy tissue.

Promatix has not disclosed timelines for IND-enabling studies or first-in-human dosing. The company said it is developing a pipeline of bispecific ADCs in colorectal cancer and additional solid tumour indications. Dr. Michael Hunter, CEO and co-founder of Promatix, said the PBS293-MMAE preclinical data "provide early evidence that this strategy holds the promise of developing therapies with novel mechanisms that can provide meaningful new treatment options for patients." He noted that while the ADC field has advanced in payload, linker, and conjugation chemistry, "true tumour-selective targeting remains a major challenge," and that many validated oncology targets such as EGFR are constrained by expression in healthy tissue.

Mechanism of action and Promatix Biosciences PBS293 platform rationale

PBS293-MMAE was developed using what Promatix calls its TxPro platform, a tumour surface proteomics database covering membrane proteins across multiple cancer types. The platform uses computational analytics (CipherPro) to identify tumour-selective antigen pairs, affinity-engineering capabilities (AviPro) to optimise bispecific engagement, and a functional validation framework (BiPro) for lead selection. The core principle underlying cis-bispecific antibody cancer therapy of this type is "AND-gate" logic: the ADC is engineered so that strong binding, internalisation, and payload delivery occur only when both EGFR and EphA2 are co-expressed on the surface of the same cell. This hybrid avidity mechanism is designed to ensure that cells expressing only one of the two antigens — as is the case for most healthy tissues — experience minimal drug engagement, thereby widening the therapeutic window.

The rationale for targeting EGFR and EphA2 together in colorectal cancer rests on their frequent co-expression in CRC tumour cells. EGFR is among the most clinically validated targets in CRC, with approved monoclonal antibodies cetuximab and panitumumab used in the metastatic setting. However, benefit from these agents is restricted to patients with RAS wild-type, left-sided tumours — approximately 15% of the overall CRC population, according to published literature cited by Promatix. Patients with KRAS or BRAF mutations, or right-sided disease, derive little to no benefit from EGFR-targeted antibodies. PBS293-MMAE is designed to function independently of RAS/BRAF mutation status, potentially addressing a population for whom EGFR-directed therapy has been ineffective.

EphA2 is a receptor tyrosine kinase that is overexpressed in multiple solid tumour types and has been associated with tumour progression and metastasis. Its expression in colorectal cancer, combined with limited expression in most normal adult tissues relative to EGFR, makes it a candidate for improving the selectivity of EGFR-directed ADC approaches.

PBS293-MMAE remains unapproved in all jurisdictions and has not entered clinical testing. No US FDA designations (Fast Track, Orphan Drug, Breakthrough Therapy) have been reported for this asset.

Competitive landscape for EphA2-targeted and bispecific ADC programmes

The bispecific ADC field is expanding, though few programmes specifically combine EGFR and EphA2. No other EGFR×EphA2 bispecific ADC programme in clinical development was identified in public databases at the time of this announcement, making PBS293-MMAE a first-in-class candidate for this specific target combination. However, several programmes targeting EphA2 or employing bispecific ADC architectures in solid tumours are in various stages of development:

• Bicycle Therapeutics' BT5528, an EphA2-targeting Bicycle Toxin Conjugate, is in Phase I/II testing in patients with advanced solid tumours expressing EphA2. BT5528 uses Bicycle Therapeutics' constrained peptide platform rather than a conventional antibody scaffold, representing a distinct modality from PBS293-MMAE. Early clinical data have been published and the programme is active though not currently recruiting.

• DS-8895a, an anti-EphA2 naked antibody (not an ADC), was evaluated in a Phase I study sponsored by the Ludwig Institute for Cancer Research in patients with advanced EphA2-positive solid tumours. Published safety and bioimaging data confirmed target engagement, though the programme does not appear to have advanced beyond Phase I.

• Academic groups have explored anti-EGFR/EphA2 bispecific antibody approaches at the translational research stage, though these have not been disclosed as entering formal drug development programmes.

In the broader CRC-ADC space, several EGFR-targeted monospecific ADCs and other bispecific constructs are under investigation by larger companies, though none with the specific EGFR×EphA2 cis-bispecific architecture described by Promatix. The differentiation Promatix claims — tumour selectivity through dual-antigen requirement rather than single-target engagement — will need to be validated in human studies before its clinical relevance can be assessed.

The transition from preclinical efficacy in xenograft models to clinical activity in patients carries a well-documented attrition rate in oncology. The PBS293-MMAE preclinical data establish a mechanistic proof of concept for the hybrid avidity approach and provide a rationale for clinical development, but the absence of pharmacokinetic, pharmacodynamic, and formal toxicology data in the public domain means that the path to first-in-human testing remains opaque. For Promatix, a company that has not previously advanced an asset into the clinic, the next twelve to eighteen months — during which IND-enabling work would typically be completed — will determine whether the preclinical promise of its cis-bispecific platform translates into a viable clinical programme.

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