DARPins (Designed Ankyrin Repeat Proteins) are a non-antibody based protein scaffold which has undergone extensive clinical characterization. DARPins are small, stable proteins derived from naturally occurring ankyrin repeat proteins and are characterized by high binding affinity and specificity, and a flexible architecture enabling multispecific approaches beyond bi-specific molecules. A total of seven clinical DARPin drug candidates across therapeutic areas spanning ophthalmology (abicipar), virology (ensovibep), and oncology – including solid tumors (MP0250, MP0274, MP0310, MP0317) and hematologic neoplasms (MP0250, MP0533) – have been tested in patients, with the two most advanced reaching the registrational phase of development. Here, we systematically review the published clinical experience with DARPin therapeutics and imaging agents generated over the past decade. The DARPin drug candidates have evolved from relatively simple binders/neutralizers, with impact on specific disease hallmarks, to more sophisticated effector function-enabled molecules that modulate complex tumor-host interactions with therapeutic intent. The accumulated clinical safety, pharmacokinetics, and activity data described herein illustrate the versatility of DARPins to influence complex biological processes and thus help patients with medical conditions that are in some cases difficult to treat with other therapeutic modalities. Following recent breakthroughs in protein structure prediction and de novo protein design, DARPins are poised to deliver an array of unprecedented and exquisitely targeted novel drug candidates eagerly awaited by patients with high unmet medical needs.

The authors are employed by Molecular Partners AG and own stock of the company.

This systematic review was supported by Molecular Partners AG. All DARPin therapeutic studies except ACTIV-3 were sponsored by Molecular Partners AG. The ACTIV-3 study was partially funded by the National Institutes of Health.

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This systematic review summarized work published to date. Please see reviewed research for data availability.