Abstract
Human epidermal growth factor receptor 3 (HER3) has been increasingly scrutinized as a potential drug target since the elucidation of its role in mediating tumor growth and acquired therapy resistance. Affibody molecules are so-called scaffold proteins with favorable biophysical properties, such as a small size for improved tissue penetration and extravasation, thermal and chemical stability, and a high tolerance to modifications. Additionally, affibody molecules are efficiently produced in prokaryotic hosts or by chemical peptide synthesis. We have previously evaluated the biodistribution profiles of five mono- and bivalent anti-HER3 affibody molecules (designated as 3) fused to an albumin-binding domain (designated as A), 3A, 33A, 3A3, A33, and A3, that inhibit ligand-dependent phosphorylation. In the present study, we examined the therapeutic efficacy of the three most promising variants, 3A, 33A, and 3A3, in a direct comparison with the HER3-targeting monoclonal antibody seribantumab (MM-121) in a preclinical BxPC-3 pancreatic cancer model. Xenografted mice were treated with either an affibody construct or MM-121 and the tumor growth was compared to a vehicle group. Receptor occupancy was estimated by positron emission tomography/computed tomography (PET/CT) imaging using a HER3-targeting affibody imaging agent [68Ga]Ga-(HE)3-Z08698-NODAGA. The affibody molecules could inhibit ligand-dependent phosphorylation and cell proliferation in vitro and demonstrated tumor growth inhibition in vivo comparable to that of MM-121. PET/CT imaging showed full receptor occupancy for all tested drug candidates. Treatment with 3A and 3A3 affibody constructs was more efficient than with 33A and similar to the anti-HER3 antibody seribantumab, showing that the molecular design of affibody-based therapeutics targeting HER3 in terms of the relative position of functional domains and valency has an impact on therapeutic effect.
Highlights
New insights into tumor biology, gained from the perpetually growing field of oncology, have prompted researchers to contrive novel treatment strategies and regimens with the aim of reducing tumor burden and improving quality of life [1]
The affibody construct TAM-Human epidermal growth factor receptor 3 (HER3) delayed the growth of HER3 expressing tumors in a mouse model with equal potency as the HER3-targeting antibody MM-121 [21], indicating the main mode of action is based on receptor blocking and is not Fc-mediated
We have evaluated the influence of the molecular design of HER3-targeting monoand bivalent affibody constructs on therapeutic efficacy in a preclinical model
Summary
New insights into tumor biology, gained from the perpetually growing field of oncology, have prompted researchers to contrive novel treatment strategies and regimens with the aim of reducing tumor burden and improving quality of life [1]. Approaches include evaluating multiple specificities, valences, and combinations thereof for improved and more selective tumor targeting or for immune system co-engagement [3]. The conjugation of cytotoxic drugs has been widely used to increase potency [4], which has become even more relevant with strategies that increase the selectivity for tumor tissues, e.g., by using prodrug formats of antibodies [5,6]. In addition to monoclonal antibodies and antibody derivatives, several non-immunoglobulin scaffold affinity proteins have been developed [7]. One such scaffold is the affibody molecule, a small (approximately 7 kDa) three-helical bundle consisting of 58 amino acids based on the staphylococcal protein A derived Z-domain [8]. As a consequence of its small size, makes the scaffold an excellent probe for companion diagnostics and other imaging applications [8]
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