Stemless reverse shoulder arthroplasty: clinical and radiologic outcomes with minimum 2 years' follow-up.

BACKGROUND: Recently, a stemless reverse shoulder arthroplasty (RSA) design was developed to preserve bone stock. Clinical and radiologic studies of this design in larger cohorts with >100 patients are not frequent. The purpose of this study was to present the clinical and radiologic results of a newly developed stemless RSA implant. The hypothesis was that this design would provide similar clinical and radiologic results to other stemless implants, as well as stemmed implants. METHODS: Between September 2015 and December 2019, all patients who underwent primary RSA with a stemless Easytech prosthesis were considered eligible for inclusion in this prospective multicenter study. The minimum follow-up period was 2 years. Clinical outcomes consisted of the Constant score, adjusted Constant score, QuickDASH (short version of Disabilities of the Arm, Shoulder and Hand questionnaire) score, Subjective Shoulder Value, and American Shoulder and Elbow Surgeons shoulder score. Radiographic parameters included radiolucency, loosening, scapular notching, and specific geometric parameters. RESULTS: Stemless RSA was performed in 115 patients (61 women and 54 men) at 6 different clinical centers. The average age at the time of surgery was 68.7 years. The average Constant score was 32.5 preoperatively and showed significant improvement to 61.8 at latest follow-up (P < .001). The Subjective Shoulder Value also demonstrated significant improvement postoperatively (from 27.0 to 77.5, P < .001). Scapular notching was observed in 28 patients (24.3%); humeral loosening, 5 (4.3%); and glenoid loosening, 4 (3.5%). The total complication rate was 17.4%. Eight patients (4 women and 4 men) underwent implant revision. CONCLUSION: The clinical outcomes of the examined stemless RSA seem to be comparable to those of other humeral designs; however, the complication and revision rates are higher than those of historical controls. Surgeons should proceed with caution when using this implant until longer-term follow-up data are available.

Use of a locking stem for reverse shoulder arthroplasty is a rare but reliable option.

INTRODUCTION: RSA is widely used in the treatment of complex trauma or degenerative changes of the shoulder. Strong primary fixation of the stem is necessary to prevent any loosening of the stem and subsequent revision. Presently, cement fixation or press-fit fixation are two options for humeral fixation, though each has its own limitations and risks. The aim of the current study is to evaluate the effectiveness of an alternative option involving a distal screw interlocking system for fixation of the humeral stem from initial implantation. METHODS: We performed a retrospective multicenter study of patients implanted with the Humelock Reversed® stem RSA that can be locked with distal humeral screws in cases of operative poor press fit or to modulate the lengthening of the arm via prosthetic humeral height. Seventy-two patients with a minimum two year follow-up were included, 13 for acute trauma, 42 for degenerative changes, and 17 for revision surgery. RESULTS: No difference was seen in radiological or clinical results for patients with or without interlocking screw primary stabilization. For non-trauma patients, the mean raw Constant score improved significantly from 31 (± 12) to 71 (± 12). For trauma patients, the mean raw Constant score for trauma (63.4) was significantly lower than for non-trauma cases (72.1) (p < 0.001). Analysis of the filling ratio demonstrated that interlocking screws were not used for lower filling ratios and that midterm fixation of the stem is not negatively impacted by distal interlocking screw fixation. DISCUSSION: Even if use of a distal interlocking screw fixation system is rare, it can be useful for patients with poor quality fixation of stemmed RSA. CONCLUSION: Use of an interlocking screw system to stabilize the stem in RSA provides good immediate and midterm stability of the implant allowing for clinical and radiological outcomes comparable to those obtained with press-fit fixation alone.

Selective antibody intervention of Toll-like receptor 4 activation through Fc γ receptor tethering.

Inflammation is mediated mainly by leukocytes that express both Toll-like receptor 4 (TLR4) and Fc γ receptors (FcγR). Dysregulated activation of leukocytes via exogenous and endogenous ligands of TLR4 results in a large number of inflammatory disorders that underlie a variety of human diseases. Thus, differentially blocking inflammatory cells while sparing structural cells, which are FcγR-negative, represents an elegant strategy when targeting the underlying causes of human diseases. Here, we report a novel tethering mechanism of the Fv and Fc portions of anti-TLR4 blocking antibodies that achieves increased potency on inflammatory cells. In the presence of ligand (e.g. lipopolysaccharide (LPS)), TLR4 traffics into glycolipoprotein microdomains, forming concentrated protein platforms that include FcγRs. This clustering produces a microenvironment allowing anti-TLR4 antibodies to co-engage TLR4 and FcγRs, increasing their avidity and thus substantially increasing their inhibitory potency. Tethering of antibodies to both TLR4 and FcγRs proves valuable in ameliorating inflammation in vivo. This novel mechanism of action therefore has the potential to enable selective intervention of relevant cell types in TLR4-driven diseases.

IL-17F co-expression improves cell growth characteristics and enhances recombinant protein production during CHO cell line engineering.

The generation of a high productivity cell line is a critical step in the production of a therapeutic protein. Many innovative engineering strategies have been devised in order to maximize the expression rate of production cells for increased process efficiency. Less effort has focused on improvements to the cell line generation process, which is typically long and laborious when using mammalian cells. Based on unexpected findings when generating stable CHO cell lines expressing human IL-17F, we studied the benefit of expressing this protein during the establishment of production cell lines. We demonstrate that IL-17F expression enhances the rate of selection and overall number of selected cell lines as well as their transgene expression levels. We also show that this benefit is observed with different parental CHO cell lines and selection systems. Furthermore, IL-17F expression improves the efficiency of cell line subcloning processes. IL-17F can therefore be exploited in a standard manufacturing process to obtain higher productivity clones in a reduced time frame.

Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis.

Interleukin-15 (IL-15) is a critical regulator of immune responses, especially at mucosal interfaces within the gastro-intestinal tract. Here, we describe the discovery and characterization of a humanized antibody to IL-15. Data from its epitope and mode of action, cell biology and primate pharmacology, as well as translational studies in human samples and in vivo proof-of-concept experiments in mouse models demonstrate the therapeutic potential of this new antibody targeting IL-15 for refractory celiac disease and eosinophilic esophagitis.

Trapezium excision and ligament reconstruction with abductor pollicis longus for basal arthritis of the thumb.

Symptomatic arthritis of the trapeziometacarpal joint is frequent. Trapeziectomy and ligamentoplasty with the abductor policis longus, that is a suspensionplasty, gives good results and can last for a long time.

Antibody Engineering.

Advanced molecular biology techniques developed during the past few decades have allowed the industry to exploit and commercialize the natural defense mechanisms that antibodies provide. This review discusses the latest advances in antibody-engineering technologies to enhance clinical efficacy and outcomes. For the constant regions, the choice of the antibody class and isotype has to be made carefully to suit the therapeutic applications. Engineering of the Fc region, either by direct targeted mutagenesis or by modifying the nature of its N-glycan, has played an important role in recent years in increasing half-life or controlling effector functions. The variable regions of the antibody are responsible for binding affinity and exquisite specificity to the target molecule, which together with the Fc determine the drug's efficacy and influence the drug dose required to obtain the desired effectiveness. A key requirement during antibody development is therefore to affinity mature the variable regions when necessary, so that they bind the therapeutic target with sufficiently high affinity to guarantee effective occupancy over prolonged periods. If the antibody was obtained from a non-human source, such as rodents, a humanization process has to be applied to minimize immunogenicity while maintaining the desired binding affinity and selectivity. Finally, we discuss the next next-generation antibodies, such as antibody-drug conjugates, bispecific antibodies, and immunocytokines, which are being developed to meet future challenges.

Chemokine receptor antagonist development.

This chapter describes assays that focus on the characterization of compounds identified in high--throughput screening campaigns, and the subsequent medicinal chemistry programs. They cover methods to determine potency in buffer, the effect of whole blood on the compounds' activity and finally the pharmacokinetic (PK)/pharmacodynamic (PD) -relationship of the compounds in a rodent species.

Bispecific antibodies: molecules that enable novel therapeutic strategies.

Bispecific antibodies are unique in the sense that they can bind simultaneously two different antigens. This property enables the development of therapeutic strategies that are not possible with conventional monoclonal antibodies. The large panel of imaginative bispecific antibody formats that has been developed reflects the strong interest for these molecules. Although in many cases the manufacturing of clinical grade material remains challenging, several bispecific antibody formats are currently in clinical trials.

Pivotal involvement of Fcgamma receptor IIA in the neutralization of lipopolysaccharide signaling via a potent novel anti-TLR4 monoclonal antibody 15C1.

The mammalian Toll-like receptor (TLR) family has evolved to sense pathogens in the environment and protect the host against infection. TLR4 recognizes lipopolysaccharide (LPS) from Gram-negative bacteria and induces a signaling cascade that, when exaggerated, has been associated with severe sepsis. We have generated a TLR4-specific monoclonal antibody, 15C1, which neutralizes LPS-induced TLR4 activation in a dose-dependent manner. 15C1 potently blocks the effects of LPS on a panel of primary cells and cell lines in vitro. The binding of 15C1 was mapped to an epitope in the second portion of the extracellular region of TLR4, which has been shown previously to be functionally important in the recognition of LPS. Furthermore, we demonstrate a novel mechanism of inhibition, as the effects of 15C1 are partially Fc-dependent, involving the regulatory Fcgamma receptor IIA (CD32A). In addition to introducing 15C1 as a potent clinical candidate for use in the treatment of LPS-mediated indications, our work demonstrates a newly discovered pathway whose manipulation is pivotal in achieving optimal neutralizing benefit.

A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts.

Interaction of insulin-like growth factor receptor I (IGF-IR) with its ligands has been reported to induce cell proliferation, transformation and blockade of cell apoptotic functions. IGF-IR is overexpressed on numerous tumor cell types and its blockade could be of importance for anti-cancer therapy. We have generated a humanized anti-IGF-IR antibody h7C10 that blocks in vitro IGF-I and IGF-II-induced cell proliferation of MCF-7 breast cancer cells. Analysis of the IGF-I transduction cascade demonstrated that the humanized anti-IGF-IR antibody and its murine parental form block IGF-I-induced tyrosine phosphorylation, both its beta-chain and IRS-1 tyrosine phosphorylation. This presumably leads to cell cycle arrest and, consequently, growth inhibition. Treatment of nude mice bearing either human breast cancer cells (MCF-7) or non small lung cancer cells (A549) with h7C10, or its murine parental form 7C10, inhibited significantly tumor growth. An almost complete inhibition of A549 tumor growth was observed when mice were treated with the anti-IGF-IR antibody combined with either a chemotherapeutic agent, Vinorelbine or an anti-epidermal growth factor receptor (EGFR) antibody, 225. Combined therapy prolonged significantly the life span of mice in an orthotopic in vivo model of A549; the combination of the anti-IGF-IR antibody with an anti-EGFR antibody was superior to the Vinorelbine combination. The present results indicate that the humanized anti-IGF-IR antibody h7C10 has a great potential for cancer therapy when combined with either a chemotherapeutic agent or an antibody that targets other growth factor receptors, such as the epidermal growth factor receptor.