single domain antibody / Ghent University - LARVOL DELTA

Interpreting High Levels of Unfolded Von Willebrand Factor in Patients with the Antiphospholipid Syndrome (ASH 2024) - "Unfolded VWF levels were measured using a llama-derived single-domain antibody (VHH) directed against a cryptic epitope in the A1 domain of VWF, which is only exposed upon unfolding of VWF...For non-APS, non-thrombosis AID a 3.7-fold higher OR was found. These data suggest an additive effect of the auto-immune disease component and the thrombosis component of the APS pathology, resulting in a stronger association of high unfolded VWF levels and APS, although this needs to be confirmed in other populations."

Clinical • Cardiovascular • Genetic Disorders • Hematological Disorders • Immunology • Inflammatory Arthritis • Thrombosis • GPI

Development of a camelid single-domain antibody-based antigen detection assay for the pan-specific diagnosis of active human and animal Trypanosoma brucei infections. (PubMed, J Clin Microbiol) - "Our approach not only enables accurate diagnosis but also offers a way to monitor treatment success. This work provides a valuable tool for disease control efforts and could help improve the health of both humans and animals in regions where trypanosomiasis is endemic."

Journal • Infectious Disease • Narcolepsy • Sleep Disorder

Single-domain antibodies directed against hemagglutinin and neuraminidase protect against influenza B viruses. (PubMed, Nat Commun) - "A second single-domain antibody broadly inhibits influenza B neuraminidase activity, including an oseltamivir-resistant neuraminidase, and its complex with neuraminidase elucidated by single particle cryo-EM established that it binds to residues in the neuraminidase catalytic site. These single-domain antibodies, fused to a human IgG1-Fc domain, fully protected female mice against an otherwise lethal influenza B virus challenge. Our findings underscore the potential of engineered single-domain antibodies to help control influenza B virus infections."

Journal • Infectious Disease • Influenza • Respiratory Diseases

Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base. (PubMed, Nat Commun) - "This VHH-based antibody with a highly potent mechanism of antiviral action forms the basis for a new class of pan-sarbecovirus neutralizing biologics, which are currently under development. In addition, the unique quaternary binding mode of the VHHs to the prefusion HR2 could be exploited for other class I fusion proteins."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody. (PubMed, Elife) - "Here, we report the serendipitous discovery of a camelid single-domain antibody (sdAb aka Nanobody) that selectively inhibits the enzymatic activity of trypanosomatid (but not host) pyruvate kinases through an allosteric mechanism. By combining enzyme kinetics, biophysics, structural biology, and transgenic parasite survival assays, we provide a proof-of-principle that the sdAb-mediated enzyme inhibition negatively impacts parasite fitness and growth."

Journal

Development of nanobodies against the coat protein of maize chlorotic mottle virus. (PubMed, FEBS Open Bio) - "Eleven MCMV-specific nanobodies were identified and shown to detect MCMV in infected maize plants. Thus, our results show that nanobodies isolated from llama immunized with MCMV CP can distinguish infected and healthy maize plants, potentially enabling development of affordable MCMV detection protocols."

Journal

High efficacy of huCD20-targeted AcTaferon in humanized patient derived xenograft models of aggressive B cell lymphoma. (PubMed, Exp Hematol Oncol) - "The huCD20-Fc-AFN consists of a huCD20-specific single-domain antibody (VHH) linked through a heterodimeric 'knob-in-hole' human IgG1 Fc molecule to an attenuated huIFNα2 sequence...In humanized mice, there was a trend for increased survival when compared to equimolar rituximab (mOS 49 to 80 days; HR = 0.73; p = 0.09). The antitumoral effects of huCD20-Fc-AFN were partly due to direct effects of type I IFN on the tumor cells, but additional effects via the human immune system are essential to obtain long-term remissions. To conclude, huCD20-Fc-AFN could provide a novel therapeutic strategy for huCD20-expressing aggressive B-NHLs."

Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • IFNA1

Generation and Characterization of Novel Pan-Cancer Anti-uPAR Fluorescent Nanobodies as Tools for Image-Guided Surgery. (PubMed, Adv Sci (Weinh)) - "Additionally, rapid and accurate tumor localization and demarcation are demonstrated in an orthotopic human glioma model. Utilizing these Nbs can potentially enhance the precision of surgical tumor resection and, consequently, improve survival rates in the clinic."

Journal • Pan tumor • Surgery • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor

AXL-specific single domain antibodies show diagnostic potential and anti-tumor activity in Acute Myeloid Leukemia. (PubMed, Theranostics) - "Using these in vitro models, its anti-tumor effect was evaluated as a single agent, and in combination with standard of care agents venetoclax or cytarabine. Because of their diagnostic potential, sdAbs could be used to screen patients eligible for AXL-targeted therapy and to follow-up AXL expression during treatment and disease progression. When fused to an Fc-domain, sdAbs acquire additional therapeutic properties that can lead to a multidrug approach for the treatment of AXL-positive cancer patients."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AXL • GAS6

Sustained release of a human pd-l1 single-domain antibody using peptide-based hydrogels. (PubMed, Eur J Pharm Biopharm) - "Additionally, after encapsulation in the hydrogel and s.c. administration, a significantly extended systemic presence and tumor uptake of K2 was observed in mice bearing a melanoma tumor expressing human PD-L1. Altogether, this study describes how peptide hydrogels can be exploited to provide the sustained release of sdAbs, thereby potentially enhancing its clinical and therapeutic effects."

Journal • Melanoma • Oncology • Solid Tumor • PD-1 • PD-L1

Promises and challenges of single-domain antibodies to control influenza. (PubMed, Antiviral Res) - "SdAbs directed against influenza A matrix protein 2 or its ectodomain have been reported, while no sdAbs have been described targeting the influenza B matrix protein 2. Known for their high specificity, ease of production and formatting, sdAb-based antivirals could be a major leap forward in influenza control."

Journal • Review • Infectious Disease • Influenza • Respiratory Diseases

A neutralizing single-domain antibody that targets the trimer interface of the human metapneumovirus fusion protein. (PubMed, mBio) - "This suggests that hMPV pre-F undergoes trimer opening or "breathing" on infectious virions, exposing a vulnerable site for neutralizing antibodies. Finally, we show that this single-domain antibody, fused to a human IgG1 Fc, can protect cotton rats against hMPV replication, an important finding for potential future clinical applications."

Journal

Safety assessment of fluorescently labeled anti-EGFR Nanobodies in healthy dogs. (PubMed, Front Pharmacol) - "Images of the oral mucosa, acquired with a fluorescence imaging device (Fluobeam), suggest rapid clearance, which was in accordance with previous in vivo studies. These are the first results to indicate that 7D12-s775z is well tolerated in dogs and paves the way to conduct clinical trials in canine patients with EGFR-overexpressing spontaneous tumors."

Journal • Oncology • Solid Tumor

Isolation of single-domain antibodies that potently neutralize SARS coronaviruses through binding to a quaternary epitope in spike heptad repeat 2. (ESWI 2023) - No abstract available

Infectious Disease • Novel Coronavirus Disease

Nanobodies: a promising tool to perturb ApoE4 activity in Alzheimer’s disease pathology (AAIC 2023) - "Single domain antibodies or nanobodies are versatile tools to reveal new information on apoE4 and its pathological effects in AD... Nanobodies are excellent tools to uncover new biological information concerning apoE4."

Alzheimer's Disease • CNS Disorders • APOE

GlycoVHH: optimal sites for introducing N-glycans on the camelid VHH antibody scaffold and use for macrophage delivery. (PubMed, MAbs) - "A VHH carrying predominantly a ManGlcNAc N-glycan at one of these preferred sites showed highly efficient, glycan-dependent uptake by Mf4/4 macrophages in vitro and by alveolar lung macrophages in vivo, illustrating one potential application of glyco-engineered VHHs: a glycan-based targeting approach for lung macrophage endolysosomal system delivery. The set of optimal artificial VHH N-glycosylation sites identified in this study can serve as a blueprint for targeted glyco-engineering of other VHHs, enabling site-specific functionalization through the rapidly expanding toolbox of synthetic glycobiology."

Journal

CILTACABTAGENE AUTOLEUCEL (CILTA-CEL) B-CELL MATURATION ANTIGEN (BCMA)-DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL (CAR-T) THERAPY IN PATIENTS WITH EARLY RELAPSE AFTER INITIAL MULTIPLE MYELOMA (MM) THERAPY (EBMT 2022) - P2 | "Clinical Trial Registry: NCT04133636 Background: Cilta-cel is a CAR-T therapy with 2 BCMA targeting, single-domain antibodies...A single cilta-cel infusion (target dose of 0.75×106 CAR+ viable T cells/kg) was given 5–7 days after start of lymphodepletion (300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine)... A single cilta-cel infusion led to early and deep responses and early achievement of MRD negativity in patients experiencing early clinical relapse/treatment failure to initial MM therapy. Findings support exploration of cilta-cel in earlier lines of treatment and incorporation into potentially curative frontline regimens for MM patients."

CAR T-Cell Therapy • Clinical • Anemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Leukopenia • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia • Transplantation

Site-Specific Fluorescent Labeling, Single-Step Immunocytochemistry, and Delivery of Nanobodies into Living Cells. (PubMed, Methods Mol Biol) - "The smallest natural antibody fragments currently available are single-domain antibodies obtained from camelid species and sharks (variable new antigen receptors)...Also described are methods for delivery of fluorescent nanobodies into the cytoplasm of mammalian cells by photoporation, a very low-toxicity approach involving laser light and graphene quantum dots. The combined protocol embodies a novel route for studying protein function in living cells at high resolution."

Journal

Selective IL-1 activity on CD8 T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication. (PubMed, J Immunother Cancer) - "Our data illustrate that anticancer cellular immunity can be safely promoted with an IL-1β-based AcTakine, which synergizes with other immunotherapies for efficient tumor destruction."

IO biomarker • Journal • Cutaneous Melanoma • Immunology • Lung Cancer • Melanoma • Oncology • Solid Tumor • CD8 • IFNG • IL1B • TNFA

CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma. (PubMed, Oncoimmunology) - "In addition, we observed an increase in CD8 T-cells and more overall PD-L1 expression on immune and non-immune cells, implying an interferon gamma signature using actinium-225 labeled CS1-directed sdAbs. In this proof-of-principle study, we highlight, for the first time, the therapeutic potential and immunomodulating effects of anti-CS1 radionuclide therapy to target residual MM cells."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • CD8 • IFNG • PD-L1

Formatting and gene-based delivery of a human PD-L1 single domain antibody for immune checkpoint blockade. (PubMed, Mol Ther Methods Clin Dev) - "Monoclonal antibodies that target the inhibitory immune checkpoint axis consisting of programmed cell death protein 1 (PD-1) and its ligand, PD-L1, have changed the immune-oncology field. K2-Fc was significantly better than avelumab in enhancing tumor cell killing in the 3D melanoma model. Overall, this study describes K2-based immune checkpoint medicines, and it highlights the benefit of an IgG1 Fc fusion to K2 that gains bivalency, effector functions, and efficacy."

Checkpoint inhibition • Journal • Gene Therapies • Immune Modulation • Inflammation • Melanoma • Oncology • Solid Tumor • PD-1

Improving the yield of recalcitrant Nanobodies® by simple modifications to the standard protocol. (PubMed, Protein Expr Purif) - "Nanobodies are single-domain antibody constructs derived from the variable regions of heavy chain only (VH) camelid IgGs...The periplasmic extraction protocol was also changed to ensure efficient osmolysis, prevent both protein degradation and prevent downstream chelation of Ni ions during IMAC purification. Adoption of this protocol will lead to an improvement of the expression of Nanobodies in general, and specifically, those that are recalcitrant."

Clinical • Journal • Targeted Protein Degradation

[VIRTUAL] TEACHING AN OLD DOG NEW TRICKS: ACTIVITY-ON-TARGET INTERFERON TO TREAT T-ALL (EHA 2020) - "Mutated IFNa2Q124R, with a strongly reduced affinity for its receptor complex, was fused to single domain antibodies targeting cell-specific domains, which selectively restores the AcTaferon (AFN) activity in a cell-type specific manner...No synergism was observed between asparaginase and the indirect immune-mediated Clec9A-AFN anti-leukemic effect. Conclusion In conclusion, we have developed novel optimized immunocytokines as an off-the-shelve targeted immunotherapy for T-ALL."

IO Biomarker • Hematological Disorders • Hematological Malignancies • Oncology • Transplantation • CD8