First Trial of a DARPin for Cancer Shows Promising Efficacy Signal

Antibody treatments for cancers have been and continue to be widely explored and have produced clinical benefits for many types of malignancy. Building on the success of these treatments, recent efforts have also been directed toward the development of designed ankyrin repeat proteins (DARPins), which are smaller proteins that consist of engineered ankyrin domains with high target affinity connected by linker amino acid residues. In a phase I clinical trial that was the first to evaluate a DARPin for patients with cancer, Baird and colleagues evaluated the use of the DARPin MG0250 in 45 patients with heavily pretreated advanced solid tumors. MG0250 contains two human serum albumin binding domains, which may extend plasma half-life, along with a VEGF binding domain and a hepatocyte growth factor (HGF) binding domain. Consistent with blockade of the VEGF and HGF pathways, the most common adverse events were hypertension, proteinuria, and diarrhea co-occurring with nausea; additionally, one fatal cardiac failure event occurred, and the role of MG0250 as a contributing factor could not be ruled out. The DARPin showed preliminary signs of efficacy: Among the 40 patients for whom treatment response was evaluable, one patient (3%) with anal cancer and lung metastases experienced an unconfirmed partial response, 24 patients (60%) had stable disease for a median duration of 18 weeks, and 15 patients (38%) had progressive disease. In summary, this first-in-human trial demonstrates the potential of DARPins as a class of treatment for cancer and hints at a possible future role of this group of antibody alternatives, which have several advantages, such as being producible by purification from bacteria.

Baird RD, Linossi C, Middleton M, Lord S, Harris A, Rodón J, et al. First-in-human phase I study of MP0250, a first-in-class DARPin drug candidate targeting VEGF and HGF, in patients with advanced solid tumors. J Clin Oncol 2021;39:145–54.

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