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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.

Purpose: Biotherapeutics are a large and rapidly growing class of drugs being produced by pharmaceutical companies to treat a diverse range of clinical indications. The overall efficacy and safety of these products can be greatly impacted by their capacity to induce undesired immune responses. This review discusses in vitro cell-based methods used to assess the T cell mediated immunogenicity risk of proteinaceous therapeutic modalities and manufacturing impurities. Methods: Here, we outline the potential sources and factors that influence immunogenicity. We present patient and product considerations that should be made in designing appropriate in vitro experiments that evaluate T cell epitopes capable of triggering treatment and outcome impacting anti-drug antibody responses and other adverse events. Results: We present the current in vitro assays used to assess T cell activation towards biotherapeutics and the product impurities. Lastly, we outline the caveats, concerns, and challenges that remain with these cell-based assays. Conclusions: Data generated from these in vitro antigenicity/immunogenicity assays may be used to derive immunogenicity risk assessments for programs and production processes and provides an opportunity for early selection of candidates or manufacturing impurities with lower likelihood of generating or exacerbating clinical immunogenicity. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a relapsing-remitting chronic inflammatory disorder affecting the mucosal surface in a continuous manner from the rectum through part of, or the entire, colon. Patients with severe disease and those who become refractory or intolerant to corticosteroids and/or immunosuppressants, require treatment with biologic agents that target tumor necrosis factor-α (TNF). Golimumab, a fully human monoclonal antibody, is the latest TNF antagonist to get approved for the treatment of moderate-to-severe UC. Subcutaneously administered golimumab induces and maintains clinical response, remission, and mucosal healing. Serum concentrations of golimumab are associated with response to therapy, as patients with higher drug exposure are more likely to achieve these outcomes. Since various patient and disease-related factors were shown to influence the pharmacokinetics of TNF antagonists, drug exposure may be variable over time and between patients, affecting success of therapy. A major contributing factor is immunogenicity, with development of anti-drug antibodies (ADAb) and an accelerated clearance of drug as a result. Although there is a growing body of evidence to support therapeutic drug monitoring (TDM) for infliximab and adalimumab, two other TNF antagonists, only limited data is available for golimumab. In addition, the clinically important drug exposure thresholds are not widely known, which has limited the use of TDM for golimumab in clinical practice. This review summarizes available data regarding the use of golimumab for UC, with emphasis on the pharmacokinetics, exposure-response relationship, and the role of TDM in optimizing therapy. [ABSTRACT FROM AUTHOR]

With the advent of biologicals, more and more therapeutics are available that specifically address specific switch points in the pathomechanism of immunologically dominated diseases. Thus, the focus of diagnostics and therapy (precision medicine) is more on the individual disease characteristics of the individual patient. Regarding the different phenotypes of atopic diseases, severe asthma was the first entity for which biologicals were approved, followed by urticaria, and finally atopic dermatitis and chronic rhinosinusitis with nasal polyps. Experience in the treatment of severe bronchial asthma has shown that the intensity of the response to biological therapy depends on the quality of clinical and immunological phenotyping of the patients. This also applies to different diseases of the atopic form, as patients can suffer from several atopic diseases at the same time, each with different characteristics. Biologics are already emerging that may represent a suitable therapy for allergic bronchial asthma, which often occurs together with severe neurodermatitis, and chronic rhinosinusitis with nasal polyps. In practice, however, the question of possible combinations of biologicals for the therapy of complex clinical pictures of individual patients is increasingly arising. In doing so, the side effect profile must be taken into account, including hypersensitivity reactions, whose diagnostic and logistical management must aim at a safe and efficient therapy of the underlying disease. Increased attention must also be paid to biological therapy in pregnancy and planned (predictable) vaccinations as well as existing infections, such as SARS-CoV-2 infection. Before starting a biological therapy, the immune status should be checked with regard to chronic viral and bacterial infections and, if necessary, the vaccination status should be refreshed or missing vaccinations should be made up for before starting therapy. Currently, reliable data on the effect of biologicals on the immunological situation of SARS-CoV-2 infection and COVID-19 are not available. Therefore, research and development of suitable diagnostic methods for detection of immunologically caused side effects as well as detection of potential therapy responders and non-responders is of great importance., (© Dustri-Verlag Dr. K. Feistle.)