Promatix Biosciences Ltd has announced positive preclinical data for its first-in-class bispecific antibody–drug conjugate, PBS293-MMAE, demonstrating enhanced tumour selectivity, improved suppression and reduced toxicity in colorectal cancer models.
Promatix Biosciences Ltd, a UK-based biotechnology company, has announced positive preclinical data on its lead oncology candidate, PBS293-MMAE, at the World ADC London Summit, highlighting a potential new approach for improving tumour selectivity in colorectal cancer treatment.
The company is developing a new generation of cancer therapies based on cis-bispecific antibody–drug conjugates (ADCs). Its lead molecule, PBS293-MMAE, is described as a first-in-class bispecific ADC designed for the treatment of colorectal cancer.
Addressing a longstanding challenge in ADC development
PBS293-MMAE was developed using Promatix’s proprietary proteomics-driven discovery platform, which systematically analyses tumour and normal tissue surface proteins to identify novel anti-tumour antigen pairs. The strategy enables cis-bispecific ‘AND-gate’ targeting through hybrid avidity, meaning strong binding occurs only when both target antigens are present on the same tumour cell. This is intended to improve efficacy while reducing toxicity compared with conventional ADCs.
The ADC field has made significant progress in payload, linker and conjugation chemistry, yet true tumour-selective targeting remains a major challenge.
“The ADC field has made significant progress in payload, linker and conjugation chemistry, yet true tumour-selective targeting remains a major challenge,” said Dr Michael Hunter, CEO and Co-Founder of Promatix. “Many of the most validated oncology targets, such as EGFR, are also expressed in healthy tissue, which can constrain the therapeutic window and limit efficacy. By utilising our unique capability to identify differentiated antigen pairings and engineering ADCs that depend on dual engagement, we aim to improve selectivity, enhancing both efficacy and safety across novel and validated targets.”
Dual targeting of EGFR and EphA2
PBS293-MMAE targets EGFR and EphA2, two proteins shown to be co-expressed in colorectal cancer cells. While EGFR is a clinically validated target in colorectal cancer, therapeutic antibodies such as cetuximab benefit only a subset of patients and are associated with toxicity due to widespread EGFR expression in healthy tissues.
The data demonstrated high levels of membrane co-localisation of EGFR and EphA2 in patient-derived colon cancer xenograft tissue, based on proteomic and fluorescence-activated cell sorting analyses, supporting the biological rationale for dual-target engagement.
Hybrid avidity-dependent engagement of both antigens was confirmed for PBS293-MMAE in a range of studies, including cell binding, payload internalisation and cytotoxicity assays.
Enhanced tumour suppression and reduced toxicity
In HCT116 colorectal cancer cells, PBS293-MMAE showed low-nanomolar potency more than 50-fold greater than cetuximab-MMAE. In xenograft models, the candidate achieved significantly higher dose-dependent tumour growth inhibition and sustained tumour suppression compared with cetuximab-MMAE.
Importantly, the therapy also demonstrated substantially lower cytotoxicity in normal human keratinocytes compared with cetuximab-MMAE, suggesting a reduced risk of skin toxicity and supporting its tumour-selective design.
Expanding options in metastatic colorectal cancer
PBS293-MMAE is a full IgG1 cis-bispecific ADC in development for advanced colorectal cancer, including metastatic disease. While monoclonal antibodies targeting EGFR such as cetuximab are effective in only around 15 percent of patients, the new candidate is designed to address a broader population, independent of RAS or BRAF mutation status and including right-sided tumours where current treatments are often ineffective.
PBS293-MMAE is a full IgG1 cis-bispecific ADC in development for advanced colorectal cancer, including metastatic disease.
Promatix is advancing a broader pipeline of bispecific ADCs across colorectal cancer and other solid tumours, supported by its TxPro tumour surface proteomics database and integrated computational and validation platforms.
Full results were presented in a poster entitled Hybrid Avidity–Gated EGFR/EphA2 Bispecific ADC Enables Tumour Selectivity and Keratinocyte Sparing, which is available via the company’s website.
