The biopharmaceutical industry has seen a revolutionary transformation in the development of therapeutic antibodies in recent decades. However, traditional IgG monoclonal antibodies have faced significant challenges as oral therapies due to their large size and sensitivity to gastrointestinal degradation. In contrast, VHH antibodies, derived from camelids, have emerged as a promising solution. These smaller, modular antibody domains offer the potential for enhanced stability and functionality in oral therapeutic applications. Research indicates that VHHs are both stable and more resistant to extreme conditions, making them better suited for oral delivery (Cong et al., 2024).
IgG monoclonal antibodies degrade in harsh conditions
The major challenge with traditional IgG monoclonal antibodies for oral administration is their susceptibility to the harsh conditions of the gastrointestinal (GI) tract, leading to degradation or denaturation before they reach the systemic circulation. This issue is further complicated by the large size of IgG antibodies, which hinders their effective absorption across the intestinal barrier. Addressing these problems is essential for enhancing drug efficacy and patient compliance and for tapping into the significant market potential of oral biologics. Furthermore, the development of effective oral antibodies could revolutionise treatment approaches across a wide range of diseases, offering new routes of administration and improved patient outcomes (Pitiot et al., 2022).
Size of IgG antibodies hinders absorption
Current approaches include the use of encapsulation technologies or chemical modifications to protect IgG antibodies from degradation in the GI tract. While these methods have shown some promise, they often result in higher dose requirements with increased production costs and they may affect the functional properties of the antibodies. Additionally, these solutions do not adequately address the fundamental issue of poor absorption due to the molecule’s size. There remains a significant unmet need for a more naturally suited antibody for oral administration (Zhu et al., 2023; Yadav et al., 2023).
VHH antibodies are small, stable and flexible
VHHs represent a novel approach to this problem. Their small size, approximately one-tenth the weight of a traditional antibody, not only allows them to resist GI degradation more effectively but also facilitates better absorption through the intestinal lining. VHH antibodies can also be engineered to enhance stability in extreme pH and temperature conditions, or against specific proteases which are common in the GI tract. This unique combination of size, stability, and flexibility during engineering, makes VHH antibodies ideal candidates for oral antibody therapies (Hoey et al., 2019).
Higher bioavailability and efficacy
VHH antibodies offer significant advantages over traditional IgG antibodies when used as oral medications. Their small size and robust structure allow them to remain intact and functional after passing through the stomach and intestines, leading to higher bioavailability and efficacy. Moreover, VHH antibodies can be produced at a lower cost and high quality. They are ideal candidates to be made in eukaryotic microbial expression systems, such as Saccharomyces cerevisiae, due to their simple structure and less stringent requirements for stability modifications. Manufacture in S. cerevisiae also enables multi-parameter optimisation using QTL technology. Beyond oral administration, VHH antibodies have potential applications in various formats, including inhalable and topical treatments, due to their versatile and durable nature (Tang et al., 2023)
VHH antibodies show promise in clinical trials
Studies have demonstrated that VHH antibodies can maintain their binding affinity and ability to neutralize targets even after exposure to low pH and digestive enzymes, which IgG antibodies cannot usually withstand without modification. Clinical trials involving VHH antibodies for oral administration have shown promising results, indicating improved patient outcomes without the need for invasive administration methods. For instance, VHH antibodies have been effectively used to neutralize botulinum neurotoxins, showcasing their robust application in clinical settings (Petersson et al., 2023, Yao et al., 2017).
A paradigm shift in antibody therapies
VHH antibodies represent a paradigm shift in the development of antibody-based therapies, particularly for oral administration. Their unique properties address some significant limitations of traditional IgG antibodies, offering a more effective and patient-friendly treatment option. As the biopharmaceutical sector continues to evolve, the next 5-10 years will likely see expanded applications of VHH-based biologics across various therapeutic areas, potentially revolutionising how we administer and develop oral antibody therapies. The continued exploration and adaptation of VHH antibodies could set new standards in the treatment and management of diseases, marking a significant milestone in the quest for more accessible and efficient biologic treatments.
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