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Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain (RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization 1 – 3 . One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies 4 . Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD–ACE2 interface and does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and—to our knowledge—rival the most potent antibodies against SARS-CoV-2 that have been produced to date. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2-binding domain and recognition of conserved epitopes that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised. Multivalent nanobodies against SARS-CoV-2 from mice engineered to produce camelid nanobodies recognize conserved epitopes that are inaccessible to human antibodies and show promise as a strategy for dealing with viral escape mutations.

Hepatitis A virus (HAV) is a common human pathogen found exclusively in primates. In a molecular and serologic study of 64 alpacas in Bolivia, we detected RNA of distinct HAV in ≈9% of animals and HAV antibodies in ≈64%. Complete-genome analysis suggests a long association of HAV with alpacas.

To expand the knowledge about common diseases in llamas and alpacas in Germany, a screening of the cases of South American camelids presented at the Clinic for Swine and Small Ruminants of the University of Veterinary Medicine Hannover, Germany from 2005 to the end of November 2021 was performed. A retrospective evaluation of necropsy reports from this period was conducted. Overall, necropsy reports were evaluated from 187 alpacas, 35 llamas and one vicuña (n = 223). A total of 50.2% of the dissected animals were thin or cachectic. Pathological alterations of the gastrointestinal tract were the most common findings (44.8%). In addition, liver changes were recorded, most frequently in adult animals. In contrast, diseases of the respiratory tract and the nervous system were found more frequently in juvenile animals. This study provides an overview of common pathologies in South American camelids in Germany and thus may help to recognise different disease symptoms at an early stage.

Tremendous effort has been expended over the past two and a half decades to understand many aspects of camelid heavy chain antibodies, from their biology, evolution, and immunogenetics to their potential applications in various fields of research and medicine. In this article, I present a historical perspective on the development of camelid single-domain antibodies (sdAbs or VHHs, also widely known as nanobodies) since their discovery and discuss the advantages and disadvantages of these unique molecules in various areas of research, industry, and medicine. Commercialization of camelid sdAbs exploded in 2001 with a flurry of patents issued to the Vrije Universiteit Brussel (VUB) and later taken on by the Vlaams Interuniversitair Instituut voor Biotechnologie (VIB) and, after 2002, the VIB-founded spin-off company, Ablynx. While entrepreneurial spirit has certainly catalyzed the exploration of nanobodies as marketable products, IP restrictions may be partially responsible for the relatively long time span between the discovery of these biomolecules and their entry into the pharmaceutical market. It is now anticipated that the first VHH-based antibody drug, Caplacizumab, a bivalent anti-vWF antibody for treating rare blood clotting disorders, may be approved and commercialized in 2018 or shortly thereafter. This elusive first approval, along with the expiry of key patents, may substantially alter the scientific and biomedical landscape surrounding camelid sdAbs and pave the way for their emergence as mainstream biotherapeutics.

Machine learning (ML) has played an increasing role in the hydrological sciences. In particular, Long Short-Term Memory (LSTM) networks are popular for rainfall–runoff modeling. A large majority of studies that use this type of model do not follow best practices, and there is one mistake in particular that is common: training deep learning models on small, homogeneous data sets, typically data from only a single hydrological basin. In this position paper, we show that LSTM rainfall–runoff models are best when trained with data from a large number of basins.

VHHs, or nanobodies, are distinguished by their compact size, high stability, and unique ability to selectively target specific epitopes. The CDR3 region in VHHs, which plays a crucial role in antigen binding, exhibits significant diversity and varies among species. This study systematically examined CDR3 length dependent patterns by analyzing NGS sequences from the PBMCs of Alpacas, Llamas and Bactrians, in conjunction with VHH structure data from the public database. VHHs from Alpacas and Llamas exhibited similar CDR3 length distributions, while Bactrian VHHs displayed significantly longer but narrower length distribution. Key sequence, structural, and VHH/antigen interaction characteristics correlated with CDR3 length were identified. Specifically, longer CDR3s were associated with a lower net charge, reduced surface hydrophobicity, and enhanced interactions with other VHH regions. Structural analyses revealed that longer CDR3s tended to adopt bent conformations with increased helical and coil structures, whereas shorter CDR3s favored extended conformations and β-sheets. Associations between CDR3 length and amino acid usage patterns within VHH sequences were also observed, including preferences at various sites and in antigen interactions. Notably, species-specific differences were apparent, with Alpaca and Llama VHHs showing more pronounced CDR3 length-dependent patterns than those from Bactrians. These findings highlight the significant impact of CDR3 length on VHH sequence, structure, and antigen interaction characteristics, providing valuable insights for VHH engineering, synthetic library design, and the development of therapeutic nanobodies optimized for targeting diverse epitopes.

Abstract Background & Significance VHHs are small and stable fragments that have great potential as therapeutics due to their small size, stability, versatility, and potential for oral administration. The traditional source of VHHs is camelids, but humanization is usually needed for therapeutic development. A human VHH library is highly desirable for the generation of therapeutic VHHs, but natural human VH domains are usually unstable as standalone units. We developed a humanoid VHH library of AI-designed sequences that both resemble camelid VHHs in terms of stability and have such high human content that humanization is no longer needed. Methods In this study, we present a fully AI-driven approach for the de novo design of a VHH phage library. Firstly, public camelid data and nearly one million private human sequences were collected. Secondly, one autoregressive AI model was trained on human data and another AI model was trained on the mixed data of humans and camels. Thirdly, the CDR1, CDR2, CDR3 regions of VHH were all generated by the mentioned two AI models. Finally, an ultra large quantity (4E10) of VHH sequences generated by AI were utilized to build the Humanoid VHH phage library. Results In order to verify the effectiveness of our method, we randomly synthesized and expressed 26 VHH antibodies from our AI based library. At the same time, 3 human VH molecules reported in previous literature were included as positive controls. First of all, the success rate of expression is 96.1%, which is much higher than 72% of Progen and 66% of ESMdesign. Secondly, the average titer is 59.6mg/L, which is 1.5 times the average value of the positive control group. Thirdly, the hydrophobicity of 80% de novo sequences is comparable to the positive control group. Moreover, the immunogenicity of all AI sequences is less than the average value of the positive control group according to our proprietary algorithms. Finally, the diversity and naturalness of the Humanoid VHH phage library are also excellent. Conclusions In conclusion, we have developed a fully AI-driven solution that could stably and massively generate human-like VHH sequences satisfying multiple requirements (including high titer, low hydrophobicity, low immunogenicity and ultra high success rate of expression, high diversity, high naturalness) simultaneously. As VHH is a powerful therapeutic fragment, our approach has the potential to accelerate nanobody and bispecific antibody drug development.

South American camelids (SACs) play an increasing role in veterinary care in Europe. Many alpacas or llamas presented to veterinarians suffer from anaemia, regularly with a packed cell volume (PCV) below 0.10 l/l, which is a life-threatening condition for the animals. This review article presents clinical and laboratory diagnostic tools for the diagnosis of anaemia in SACs. Clinical identification of anaemic animals can be performed by assessing the FAMACHA© score and the Body Condition Score (BCS), since anaemia in alpacas and llamas correlates with pale mucous membranes and a lowered BCS. Haematological examination of a blood sample can provide a more differentiated diagnosis of anaemia in SACs. A common finding is regenerative anaemia with an increased number of reticulocytes that is often caused by blood loss due to Haemonchus contortus. Changes in a blood smear from an alpaca or llama with regenerative anaemia may include normoblasts (nucleated red blood cells), anisocytosis, poikilocytosis, polychromasia, Howell-Jolly bodies or basophilic stippling. Furthermore, non-regenerative anaemia, often caused by trace element deficiency or cachexia, can also occur.