Bispecific ADCs: are dual-target ‘AND-Gate’ designs the future of tumour selectivity?

Antibody-drug conjugates (ADCs) continue to evolve as one of the most promising approaches in targeted cancer therapy, yet the fundamental challenge in advancing solid tumour ADCs remains therapeutic selectivity, not just payload potency, as described in a press release about PBS293-MMAE’s data at World ADC London Summit.

And yet, one core problem remains unresolved:

Selectivity.

This week, UK-based Promatix Biosciences presented preclinical data at the 16th World ADC London Summit on its lead candidate, PBS293-MMAE, according to the company’s press release. The molecule is described as a first-in-class cis-bispecific ADC targeting EGFR and EphA2 in colorectal cancer.

While still preclinical, the programme highlights a broader strategic question emerging in oncology:

Is the next phase of ADC innovation about stronger payloads — or smarter targeting?

PBS293-MMAE is described as a first-in-class cis-bispecific antibody-drug conjugate that targets two tumour antigens — EGFR and EphA2 — simultaneously, a design intended to improve tumour selectivity and reduce toxicity, as stated in the press release.

Instead of relying on a single antigen, where binding can occur even on healthy tissues, the cis-bispecific “AND-gate” mechanism of PBS293-MMAE requires co-expression of both antigens on the same cancer cell to achieve strong binding and internalisation, as explained in this detailed report on the ADC platform.

According to the detailed press coverage, this dual-antigen “AND-gate” concept is designed to enhance tumour selectivity, which may help address a longstanding issue with targets like EGFR: although EGFR is clinically validated, its expression in normal tissues can constrain the therapeutic window and increase toxicity.

Preclinical results highlighted by Promatix also suggest that PBS293-MMAE has significantly greater potency — reportedly more than 50-fold greater than a cetuximab-MMAE comparator in KRAS-mutant colorectal cancer cells — and superior tumour growth inhibition in xenograft studies, the preclinical data sumamry shows.

Importantly, these studies also showed substantially lower cytotoxicity against normal skin cells compared to cetuximab-MMAE — a signal consistent with the bispecific strategy’s intention to spare healthy tissue, it has been described in the same preclinical report.

The strategic question the ADC field now faces is whether biological targeting logic — such as dual engagement — can address selectivity limits more effectively than further chemical escalation of payload potency alone, a theme echoed by platform dialogues across the ADC innovation ecosystem.

If platforms like PBS293-MMAE can indeed demonstrate both improved efficacy and safety in clinical settings, this may signal a broader shift in ADC development where target architecture — not just cytotoxic strength — becomes the primary axis of innovation, as supported by market analyses of dual-target strategies.

Industry trend reports inferre that, for investors and industry strategists, this development may serve as an early indicator that the next wave of ADC competitive differentiation could come from novel target pairing approaches rather than incremental chemistry improvements, potentially reshaping pipeline valuations and BD priorities.

The coming months will be crucial as companies working on bispecific ADC designs — including but not limited to Promatix — begin to accumulate further preclinical and early clinical data that will either validate or challenge the underlying hypothesis of enhanced selectivity through dual targeting.

This article is part of PharmaceuticalDaily’s special series on the future of bispecific antibody-drug conjugates.