HyCAbs: Hybrid platform for the generation of camelid single-domain antibodies. (HyCAbs)

Antibodies (Abs) have a proven track record in biotechnology and -medicine. Most applications are based on conventional Abs (mostly IgGs), which have constituted a highly profitable market for decades. However, despite their track record, conventional Abs have their drawbacks and are ill-suited for certain applications. These shortcomings can usually be overcome by unconventional Abs found in other mammals. A prime example is provided by the Belgian discovery of a peculiar Ab subset that naturally occurs in camelids (e.g., camels, dromedaries, and llamas). In these Abs, antigen recognition is mediated by a single domain, which is why this domain is often referred to as a "single-domain antibody" (sdAb aka nanobody®). Camelid sdAbs possess unique features that are not usually found in conventional Abs: a small size (~15 kDa), an increased solubility, robust folding properties, a high intrinsic stability, poor immunogenicity, and the relative ease to tailor them (modifications according to a "plug-and-play" principle). These remarkable properties render them highly suitable for discovery, application, and valorisation in life sciences (including diagnostics and therapeutics). Importantly, the number of sdAbs in clinical trials and approved by the relevant regulatory agencies is on the rise (sdAbs are catching up with conventional Abs): in the past five years, four sdAbs have been approved for clinical use, ~50 others are currently in clinical trials, and many patents have been submitted/granted around the world. sdAbs are readily obtained through camelid immunisation or in silico designed synthetic sdAb libraries that have been shown to perform equally well. Immune and synthetic sdAb libraries each have their strengths and drawbacks and therefore complement each other. In most cases, interested parties have access to either immune or synthetic libraries but very rarely to both. Clearly, access to both library types through a hybrid platform will create a powerful synergy that can fuel discovery, innovation, and valorisation. The unique selling proposition of this project is the establishment of HyCAbs, an in-house hybrid sdAb platform based on the combined strengths of immune and synthetic libraries that can be employed to swiftly identify sdAbs against a myriad of target antigens. HyCAbs represents a continuation of the previously awarded PREPARAS project (Antigoon ID 49344). With this IOF PoC CREATE proposal, we aspire to consolidate and open this initiative up to i) UAntwerp researchers active in other life science domains and ii) interested external parties (both academic and industrial). In addition, we aim to unleash the potential of machine learning on deep sequencing data obtained from camelids to design and construct next-generation synthetic sdAb libraries by marrying our in-house sdAb expertise with the know-how of the BIOMINA core facility. The hybrid nature of HyCAbs is unique. One of its features would be to offer the interested party full flexibility in acquiring sdAbs through camelid immunisation, screening against synthetic libraries, or both. This flexibility enables the simultaneous consideration of sample amounts, time from antigen provision to binder identification, and budgetary constraints. For UAntwerp researchers, HyCAbs offers relatively cheap sdAb access with in-house IP from the start, which will add value for the university. For external parties, service agreements will be negotiated. Hence, we expect HyCAbs to provide various valorisation routes. HyCAbs presents a unique opportunity to establish a robust sdAb platform that enables discovery, innovation, and valorisation in its current form and supports low risk expansion and implementation of innovative elements in the field of sdAb technology in the future.

Keywords:THERAPEUTICS, DIAGNOSTICS, ANTIBODIES, INFECTIOUS DISEASES

Disciplines:Animal immunology, Proteins, Infectious diseases, Medical biotechnology not elsewhere classified, Applied immunology, Structural bioinformatics and computational proteomics, Immunogenetics