Abstract
Nanobodies (Nbs), the variable domains of camelid heavy chain-only antibodies, are a promising class of therapeutics or in vivo imaging reagents entering the clinic. They possess unique characteristics, including a minimal size, providing fast pharmacokinetics, high-target specificity, and an affinity in the (sub-)nanomolar range in conjunction with an easy selection and production, which allow them to outperform conventional antibodies for imaging and radiotherapeutic purposes. As for all protein theranostics, extended safety assessment and investigation of their possible immunogenicity in particular are required. In this study, we assessed the immunogenicity risk profile of two Nbs that are in phase II clinical trials: a first Nb against Human Epidermal growth factor Receptor 2 (HER2) for PET imaging of breast cancer and a second Nb with specificity to the Macrophage Mannose Receptor (MMR) for PET imaging of tumor-associated macrophages. For the anti-HER2 Nb, we show that only one out of 20 patients had a low amount of pre-existing anti-drug antibodies (ADAs), which only marginally increased 3 months after administering the Nb, and without negative effects of safety and pharmacokinetics. Further in vitro immunogenicity assessment assays showed that both non-humanized Nbs were taken up by human dendritic cells but exhibited no or only a marginal capacity to activate dendritic cells or to induce T cell proliferation. From our data, we conclude that monomeric Nbs present a low immunogenicity risk profile, which is encouraging for their future development toward potential clinical applications.One Sentence SummaryNanobodies, the recombinant single domain affinity reagents derived from heavy chain-only antibodies in camelids, are proven to possess a low immunogenicity risk profile, which will facilitate a growing number of Nanobodies to enter the clinic for therapeutic or in vivo diagnostic applications.
Highlights
Biopharmaceuticals have become increasingly important in human healthcare over the past decades
The immunogenicity risk profile was assessed by: (i) analyzing serum samples from patients enrolled in phase I for the presence of anti-drug antibodies (ADAs) with a state-of-the-art method (ECL); (ii) measuring the aggregation propensity of these Nbs; and (iii) testing their in vitro capacity to activate the key players in the immunogenicity reaction
For the ADA monitoring of the patients enrolled in the phase I positron emission tomography (PET) trial of the anti-Human Epidermal growth factor Receptor 2 (HER2) Nb tracer, first 50 healthy donors were screened for presence of ADA to determine the cut-off value of the assay, as generally recommended for ADA assays
Summary
Biopharmaceuticals have become increasingly important in human healthcare over the past decades. Preclinical safety testing on novel biopharmaceutical drug candidates is focusing on the early identification of those compounds that are more likely to provoke a strong, unwanted immune response. This will allow to either modify these problematic drug candidates or to deselect them for further investigation. The adverse clinical consequences of immunogenicity of biopharmaceuticals can be diverse and severe, including the production of anti-drug antibodies (ADAs), which may result in reduced efficacy of the drug leading to impaired treatment or altered biodistribution of an imaging tracer [2]. For safety and health reasons, investigating the immunogenicity of biopharmaceuticals (including monoclonal antibody therapeutics) forms an integrated part of the development of novel biopharmaceutical compounds
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