Inside AACR: DARPins take aim at hard-to-treat tumours

DARPin therapeutics were a prominent theme at AACR 2025, with Molecular Partners presenting a trio of preclinical programmes spanning radiopharmaceuticals and immune cell engagers. DARPins – designed ankyrin repeat proteins – are small, engineered protein scaffolds with high specificity and affinity, developed as an alternative to traditional antibodies.

Amelie Croset, Senior Director of Alliances and Partnering at the therapeutics company Molecular Partners, spoke with Drug Target Review about the science behind the presentation posters, its therapeutic potential and what is next for the platform.

“I joined Molecular Partners four years ago as the Head of Preclinical Pharmacology Platforms,” she says. “My passion for science drew me to DARPin technology, and I was eager to contribute to the development of new DARPin therapies.”

From there, things moved fast. “After 15 years in science and seeking new challenges, Molecular Partners offered me the opportunity to transition from science to business… I am very happy in my new role and look forward to supporting these collaborations and others in the future.”

And what a year to make the switch.

Three programmes, one message: DARPin modularity is here to stay

Croset’s team brought three high-profile posters to AACR, highlighting the scope and speed of their preclinical pipeline – particularly their strategic collaboration with Orano Med, now spanning 10 DARPin-based radiopharmaceuticals. “These presentations really highlight the breadth of Molecular Partners’ DARPin innovation,” says Croset, “and the progress in our strategic Radio-DARPin partnership with Orano Med, which we expanded in January.”

Let us start with the frontrunner: MP0712.

This radiopharmaceutical combines DARPin specificity with the potent cell-killing power of the alpha-emitting isotope 212Pb. MP0712 targets DLL3, a protein found in over 85 percent of small-cell lung cancers and other aggressive neuroendocrine tumours, making it a strong candidate for precision oncology.

“Our first presentation at AACR was on IND-enabling preclinical data for MP0712,” Croset explains. “The data show a high tumour uptake and a favourable safety profile… good efficacy and tumour reduction in mouse models and matching clinically-relevant DLL3 expression levels.” With an IND filing and first-in-human trials expected in 2025, MP0712 is moving steadily towards clinical evaluation.

Next in line: mesothelin

The second Radio-DARPin targets mesothelin (MSLN), a well-established but challenging antigen in ovarian cancer. One of the key obstacles in targeting MSLN is the presence of its soluble form, which can act as a therapeutic sink by binding circulating agents before they reach the tumour.

Molecular Partners has a workaround. “We have developed a DARPin with high affinity to membrane-proximal MSLN,” Croset says. “Binding of the designed membrane-proximal MSLN DARPins to tumour cells in vitro was not affected by soluble MSLN.” And in vivo? “Results show a favourable biodistribution with strong tumour accumulation… and modest accumulation in other organs.”

These findings indicate the approach is technically effective, with promising biodistribution characteristics. While still in early stages, it is clear this MSLN-targeting Radio-DARPin is laying the groundwork for broader application across peritoneal and metastatic ovarian cancer.

Switch-DARPin: turning T-cell engagers into conditional powerhouses

The third AACR presentation highlighted a CD3 Switch-DARPin platform incorporating CD2 co-stimulation – the most technically advanced of the three programmes. While T-cell engagers (TCEs) hold significant promise in oncology, their application in solid tumours has been limited by systemic toxicity and reduced T-cell functionality. The Switch-DARPin approach aims to overcome these challenges through conditional activation and enhanced T-cell support.

“Our multi-targeting Switch-DARPin T-cell engager was designed to tackle these limitations and is the first logic-gated Switch-DARPin molecule in the solid tumour setting,” Croset explains. “We boosted our MSLN CD3 DARPin T-cell engager with a CD2-engaging domain for co-stimulation. In addition, we engineered a “switchable” DARPin which can bind to EpCAM on tumour cells co-expressing MSLN or can block the CD3 DARPin, with a CD3-mask to ensure potent activation only in the presence of these tumour-associated antigens.”

This represents a tumour-specific, logic-gated mechanism of action, enhanced by integrated immune co-stimulation via CD2 engagement.

“The CD3 Switch-DARPin activates T cells specifically in the presence of cells co-expressing MSLN and EpCAM,” says Croset. “CD2 co-engagement leads to sustained T-cell activation and cytotoxic capacity, preventing T-cell dysfunction… it effectively induces significant tumour regression in vivo, without signs of T-cell activation in the periphery.”

This finding is particularly important, as it indicates that potent T-cell activation and tumour regression can be achieved without systemic immune activation – a major limitation of current T-cell engager approaches.

How do these work, technically?

If you are wondering how these DARPin molecules manage such precision, Croset has an answer. “Our Switch-DARPins are designed for targeted local and conditional activation of immune cells, and are thus intended to prevent systemic immune-cell activation,” she says.

The core idea is a modular structure: “a DARPin which has the possibility to bind to two different targets in a mutually exclusive way, depending on the biological context/environment – in other words, a two-in-one ‘Either-Or’ Switch-DARPin.”

The mechanism involves a DARPin construct in which one paratope binds a specific tumour-associated target, while the second DARPin is functionally masked. In the presence of the first target, the masking is released, enabling the second DARPin to engage its intended target. This logic-gated design ensures that activation occurs only within the tumour microenvironment, minimising off-tumour effects.

What is next?

With multiple candidates maturing in preclinical development, the pipeline’s momentum is clear. “We are making good progress across our portfolio,” Croset confirms. “The potential of our Radio-DARPins is now well recognised in the field, and we are excited for the IND submission, start of first-in-human studies and initial clinical data for our first programme MP0712… expected in 2025.”

Beyond that, the second MSLN Radio-DARPin is advancing and Switch-DARPin development is progressing further. “We will communicate specific next steps, including clinical development plans… in due time,” says Croset.

The broader strategy is clear: Molecular Partners is advancing modular DARPin platforms designed for targeted, context-dependent therapeutic applications across radiopharmaceuticals, immune cell engagers and other modalities. These efforts reflect a cohesive approach rather than isolated programmes, with potential for broad clinical impact.

Final thoughts: why it matters

Amid the noise of cancer biology and biotech buzzwords, Molecular Partners’ DARPin work feels refreshingly grounded. It centres on smart design, tighter control and ultimately more effective – and safer – treatments for patients.

“DARPin therapeutics can be tailored to specific disease biology,” says Croset, “leveraging the unique advantages of DARPins to provide leading treatments for cancer patients.”

And if AACR 2025 was any indication, those treatments are closer than we think.