TRYBE®: an Fc-free antibody format with three monovalent targeting arms engineered for long in vivo half-life.

TrYbe® is an Fc-free therapeutic antibody format, capable of engaging up to three targets simultaneously, with long half-life conferred by albumin binding. This format is shown by small-angle X-ray scattering to be conformationally flexible with favorable 'reach' properties. We demonstrate the format's broad functionality by co-targeting of soluble and cell surface antigens.

Thumb Carpometacarpal Joint Pathoanatomy-A Computed Tomography-Based Study.

 Thumb carpometacarpal joint (CMCJ) osteoarthritis is common and can lead to significant morbidity making it a condition frequently treated by hand surgeons when initial conservative measures fail. The surrounding ligamentous structures are complex and important to maintain thumb CMCJ stability.  The aim of this study was to review the normal and arthritic anatomy of the thumb CMCJ, focusing on morphology and position of osteophytes and the gap between metacarpal bases, and the effect of these on intermetacarpal ligament integrity.

Inflammatory arthritis and the elbow surgeon.

The treatment of inflammatory arthritis with disease modifying drugs and biological agents had reduced the number of patients needing surgical treatment. Surgical treatment of patients with inflammatory arthritis is challenging not only due to the factors such as bone stock and status of soft tissue but also due to the comorbidities associated with inflammatory arthritis. Multidisciplinary approach to these patients is recommended to deal with the complex poly-articular involvement and systemic physiological impairment especially when planning surgery.

Comprehensive review of surgical approaches to the elbow.

The choice of the most suitable surgical approach to the elbow forms the foundation of any successful elbow surgery. The surgical approach is based on the injury or pathology to be addressed and therefore specific anatomical details need to be considered. The surgeon must be comfortable with the bony, ligamentous and neurovascular anatomy of the elbow to consider and execute the best approach for each problem.

Role of Wrist Arthroscopy in the Management of Established Scaphoid Nonunion.

Patients with scaphoid nonunion and wrist pain may have a wide spectrum of potential concomitant pathologies that may be diagnosed and potentially managed arthroscopically. The aim of this study is to assess the usefulness of wrist arthroscopy in the assessment and treatment of scaphoid nonunion and any associated injuries. We retrospectively reviewed 34 consecutive patients with established scaphoid nonunion between January 2006 and December 2012 who had undergone arthroscopic assessment.

Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis.

Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity.

Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions.

Multivalent Fcγ-receptor engagement by a hexameric Fc-fusion protein triggers Fcγ-receptor internalisation and modulation of Fcγ-receptor functions.

Engagement of Fcγ-receptors triggers a range of downstream signalling events resulting in a diverse array of immune functions. As a result, blockade of Fc-mediated function is an important strategy for the control of several autoimmune and inflammatory conditions. We have generated a hexameric-Fc fusion protein (hexameric-Fc) and tested the consequences of multi-valent Fcγ-receptor engagement in in vitro and in vivo systems.

Fab-dsFv: A bispecific antibody format with extended serum half-life through albumin binding.

An antibody format, termed Fab-dsFv, has been designed for clinical indications that require monovalent target binding in the absence of direct Fc receptor (FcR) binding while retaining substantial serum presence. The variable fragment (Fv) domain of a humanized albumin-binding antibody was fused to the C-termini of Fab constant domains, such that the VL and VH domains were individually connected to the Cκ and CH1 domains by peptide linkers, respectively. The anti-albumin Fv was selected for properties thought to be desirable to ensure a durable serum half-life mediated via FcRn.

Extending the half-life of a fab fragment through generation of a humanized anti-human serum albumin Fv domain: An investigation into the correlation between affinity and serum half-life.

We generated an anti-albumin antibody, CA645, to link its Fv domain to an antigen-binding fragment (Fab), thereby extending the serum half-life of the Fab. CA645 was demonstrated to bind human, cynomolgus, and mouse serum albumin with similar affinity (1-7 nM), and to bind human serum albumin (HSA) when it is in complex with common known ligands. Importantly for half-life extension, CA645 binds HSA with similar affinity within the physiologically relevant range of pH 5.

Generation of Recombinant Monoclonal Antibodies from Immunised Mice and Rabbits via Flow Cytometry and Sorting of Antigen-Specific IgG+ Memory B Cells.

Single B cell screening strategies, which avoid both hybridoma fusion and combinatorial display, have emerged as important technologies for efficiently sampling the natural antibody repertoire of immunized animals and humans. Having access to a range of methods to interrogate different B cell subsets provides an attractive option to ensure large and diverse panels of high quality antibody are produced. The generation of multiple antibodies and having the ability to find rare B cell clones producing IgG with unique and desirable characteristics facilitates the identification of fit-for-purpose molecules that can be developed into therapeutic agents or research reagents.

A Rare Case of Reverse Oblique Ulnar Head and Neck Fracture.

Isolated distal ulnar head and neck fractures are rare. Undisplaced fractures are normally treated non-operatively. We report a case of a reverse oblique ulnar head and neck fracture, which despite the initial undisplaced configuration, was unstable and displaced over the subsequent weeks.

Functional Outcomes Following Pilon Fractures of the Middle Phalanx Managed with the Ligamentotaxor External Fixator.

Background: The surgical aims in managing displaced intra-articular fractures of the base of the middle phalanx include early joint reduction, maintaining congruence and early mobilization. Achieving this can be a challenge. However dynamic external fixators offer a solution.

Corrective osteotomy for malunited metacarpal fractures: long-term results of a novel technique.

Symptomatic malunited metacarpal fractures can significantly affect hand function. We retrospectively reviewed the results of our technique of corrective osteotomy in 14 malunited metacarpal fractures (12 patients) with an average age of 30 years (range 18-49) from January 2005 to December 2011. The dominant hand was involved in nine patients and all except one were male.

Management of heterotopic ossification and restricted forearm rotation after tension band wiring for olecranon fracture.

A 32-year-old lady presented to our clinic with persistent painful restriction of her dominant forearm movements for three months after tension band wiring of olecranon. She had full elbow flexion and extension; however, her forearm rotations were restricted and painful. Investigations revealed prominent tips of the wire, eroding the radial tuberosity with heterotopic ossification between the radius and ulna.

Surgical excision of ununited hook of hamate fractures via the carpal tunnel approach.

Introduction: Direct excision of a symptomatic ununited hook of hamate fracture is the gold standard, most frequently via a Guyon space approach. The open carpal tunnel approach is another option, which has not previously been commonly considered and not reported in a peer review journal. Our study aims to highlight the carpal tunnel approach as a successful technique in a consecutive series of ununited hook of hamate fractures.

The rapid generation of recombinant functional monoclonal antibodies from individual, antigen-specific bone marrow-derived plasma cells isolated using a novel fluorescence-based method.

Single B cell technologies, which avoid traditional hybridoma fusion and combinatorial display, provide a means to interrogate the naturally-selected antibody repertoire of immunized animals. Many methods enable the sampling of memory B cell subsets, but few allow for the direct interrogation of the plasma cell repertoire, i.e.

A mixture of functionally oligoclonal humanized monoclonal antibodies that neutralize Clostridium difficile TcdA and TcdB with high levels of in vitro potency shows in vivo protection in a hamster infection model.

Clostridium difficile infections are a major cause of antibiotic-associated diarrhea in hospital and care facility patients. In spite of the availability of effective antibiotic treatments, C. difficile infection (CDI) is still a major cause of patient suffering, death, and substantial health care costs.

Characterization of the interaction of sclerostin with the low density lipoprotein receptor-related protein (LRP) family of Wnt co-receptors.

LRP5 and LRP6 are proteins predicted to contain four six-bladed β-propeller domains and both bind the bone-specific Wnt signaling antagonist sclerostin. Here, we report the crystal structure of the amino-terminal region of LRP6 and using NMR show that the ability of sclerostin to bind to this molecule is mediated by the central core of sclerostin and does not involve the amino- and carboxyl-terminal flexible arm regions. We show that this structured core region interacts with LRP5 and LRP6 via an NXI motif (found in the sequence PNAIG) within a flexible loop region (loop 2) within the central core region.