Beyond Antibodies: The DARPin® Drug Platform

Abstract

The DARPin^® drug platform was established with a vision to expand the medical use of biologics beyond what was possible with monoclonal antibodies. It is based on naturally occurring ankyrin repeat domains that are typically building blocks of multifunctional human proteins. The platform allows for the generation of diverse, well-behaved, multifunctional drug candidates. Recent clinical data illustrate the favorable safety profile of the first DARPin^® molecules tested in patients. With the positive phase III results of the most advanced DARPin^® drug candidate, abicipar, the DARPin^® drug platform is potentially about to achieve its first marketing approval. This review highlights some of the key milestones and decisions encountered when transforming the DARPin^® platform from an academic concept to a biotech drug pipeline engine.

Fig. 1

Representations of a single designed ankyrin repeat domain and a multidomain DARPin^® drug candidate. a Ribbon representation of an ankyrin repeat domain (PDB ID: 1MJ0) consisting of five repeats, with randomized interaction colored in orange and a transparent surface superimposed. b Molecular model of MP0250, a DARPin^® drug candidate consisting of four DARPin^® domains (molecular weight approximately 62 kDa). The scaffold is dark blue, and the potential target interaction residues of the individual domains are orange (human serum albumin [HSA]), cyan (hepatocyte growth factor [HGF]), and red (vascular endothelial growth factor [VEGF])

Fig. 2

A schematic overview of all development-stage DARPin^® drug candidates depicted on the two dimensions “degree of novel biology” vs. “degree of novel drug concept” on the drug development programs in the context of the three-horizon strategy of Molecular Partners. A first-horizon program such as abicipar is built on known biology and takes advantage of the favorable DARPin^® drug properties for the generation of a “biobetter compound.” Second-horizon programs such as MP0250 and MP0274 are based on biology that has been validated in third-party phase II clinical trials; at the same time, they are multidomain drug candidates, a key strength of the DARPin^® platform. In third-horizon programs, biology may be less validated and novel drug concepts may be applied, as illustrated by MP0310 (see Fig. 5) and MP0317

Fig. 3

Schematic illustration of duration of action engineering of abicipar. Drug concentration of abicipar (black line) and ranibizumab (gray line) are shown over time. Assuming reference ranibizumab is administered 50 μl/0.5 mg intravitreally, and the drug has a half-life in the 1.5 ml rabbit eye of 3 days and an inhibition constant IC₅₀ of about 100 pM, then the drug would stop being efficacious when reaching a concentration equivalent to the IC₅₀, i.e. duration of action of about 48 days. Three aspects help increase the duration of action of abicipar: (I) improving the potency to lower values in combination with high drug stability ensure that the drug is also active at very low amounts; (II) engineering the half-life as such, requiring high drug stability; (III) applying higher doses. Assuming abicipar exhibits an IC₅₀ of about 25 pM [26], has an ocular half-life of 6 days in the rabbit eye, and that it can be applied at about 5.5 times the molar amounts of ranibizumab, then it would take 124 days (4 months) for the vitreal concentration of abicipar reaches the IC₅₀ concentration of 25 pM

Fig. 4

Duration of treatment of patients with MP0250 in phase I clinical trial NCT02194426. The weeks of treatment are shown for every patient of the trial, and patients are grouped in the different cohorts. Graph adapted from Azaro et al. [40]. q2w every 2 weeks, q3w every 3 weeks

Fig. 5

Schematic representation of the differentiation of localized immune cell modulator MP0310 from classical immune cell modulators. Antibodies activating immune cells via 4-1BB typically activate immune cells in the tumor as well as in healthy tissue, leading to promising efficacy linked to a problematic toxicology profile. MP0310 binds to fibroblast-activating protein (blue dots) on tumor-associated fibroblast and clusters, providing an opportunity for immune cell activation. In healthy tissue, with a lack of opportunity to cluster, immune cells are not modulated by MP0310. mAb monoclonal antibody