Objective. To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares.Methods. Patients for whom nonsteroidal antiinflammatory drugs and colchicine were not suitable treatments were enrolled in this multicenter, randomized, double-blind study with follow-up for up to 2 years. The study was designed to assess superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg in a single injection) for the primary end point of changed patient-assessed pain intensity in the most affected joint (scored on a visual analog scale of 0-100) from baseline to 24-72 hours. Secondary outcome measures included: safety, immunogenicity, and patient-and physician-assessed global response.Results. One hundred sixty-five patients were randomized to receive anakinra (n = 110) or triamcinolone (n = 55). The median age was 55 years (range 25-83), 87% were men, the mean disease duration was 8.7 years, and the mean number of self-reported flares during the prior year was 4.5. A total of 301 flares were treated (214 with anakinra; 87 with triamcinolone). Anakinra in both doses and triamcinolone provided clinically meaningful reduction in patientassessed pain intensity in the first and subsequent flares. For the first flare, the mean decline in pain intensity from baseline to 24-72 hours for total anakinra and triamcinolone was −41.2 and −39.4, respectively (P = 0.688). Anakinra performed better than triamcinolone for most secondary end points. There were no unexpected safety findings. The presence of antidrug antibodies was not associated with adverse events or altered pain reduction.Conclusion. Anakinra was not superior to triamcinolone for the primary end point, but had comparable efficacy in pain reduction and was favored for most secondary end points. Anakinra is an effective option for gout flares when conventional therapy is unsuitable.ClinicalTrials.gov identifier: NCT03002974. Supported by Swedish Orphan Biovitrum AB (Sobi).

The beneficial effect of antibody therapy in human disease has become well established mainly for the treatment of cancer and immunological disorders. The inherent monospecificity of mAbs present limitations to mAb therapy which have become apparent notably in addressing complex entities like infectious agents or heterogenic endogenous targets. For such indications mixtures of antibodies comprising a combination of specificities would convey more potent biological effect which could translate into therapeutic efficacy. Recombinant polyclonal antibodies (rpAb) consisting of a defined number of well-characterized mAbs constitute a new class of target specific antibody therapy. We have developed a cost-efficient cell banking and single-batch manufacturing concept for the production of such products and demonstrate that a complex pAb composition, rozrolimupab, comprising 25 individual antibodies can be manufactured in a highly consistent manner in a scaled-up manufacturing process. We present a strategy for the release and characterization of antibody mixtures which constitute a complete series of chemistry, manufacturing, and control (CMC) analytical methods to address identity, purity, quantity, potency, and general characteristics. Finally we document selected quality attributes of rozrolimupab based on a battery of assays at the genetic-, protein-, and functional level and demonstrate that the manufactured rozrolimupab batches are highly pure and very uniform in their composition.

Only a small population (25-30%) of human peripheral blood B lymphocytes expresses large sialoglycoprotein (LSGP) (CD43). However, in the presence of autologous T cells and pokeweed mitogen (PWM) a majority (50-90%) of the immunoglobulin-producing cells (cIg+ cells) that develop from these B cells express CD43 is detected with anti-CD43 monoclonal antibodies (MoAb) B1B6, and the proportion of CD43+cIg+ cells increases with time of culture. Furthermore, a relatively larger proportion (60-80%) of the IgG-producing cIg+ cells are CD43+ compared with IgM-containing cIg+ cells (30-50%). In human tonsils, significantly more CD43+ cells (35%) are found in the in vivo-activated fraction of B cells than in the fraction of resting B cells (5%). A majority of the cIg+ cells that develop from the resting or the in vivo-activated tonsillar B cells in a PWM-induced B-cell differentiation system are CD43+ (80-100%). Furthermore, tonsillar B cells depleted of CD43+ cells give rise to cIg+ cells, of which the majority are CD43+, and the proportion of such cells increases with time of culture (60-90%). Taken together, these results indicate that LSGP belongs to a group of B-cell membrane molecules that are induced and upregulated upon activation and differentiation.

Anakinra is an effective, well-tolerated, long-term anti-inflammatory treatment for cryopyrin-associated periodic syndromes (CAPS), yet evidence shows that it can induce the development of anti-drug antibodies (ADA). This analysis aims to determine ADA occurrence in CAPS patients and elucidate their effects on anakinra dosing and drug efficacy. A post hoc analysis was performed on data from a long-term safety and efficacy study in patients with severe CAPS. Patients were initiated on an anakinra dose of 1.0-2.4 mg/kg once daily subcutaneously, which was increased (in 0.5-1.0 mg/kg increments) to 2.0-5.0 mg/kg/day according to clinical need (median 3.1 mg/kg/day). ADA, serum amyloid A (SAA), and C-reactive protein (CRP) levels were measured at various time points, and pharmacokinetic (PK) parameters at 1 and 3 months. Efficacy was evaluated using a diary symptom sum score (DSSS), and SAA and CRP levels were evaluated as proxies of efficacy. Safety was evaluated by an analysis of adverse events (AEs). Anakinra dose levels were unrelated to ADA status. A high proportion of patients with at least one post-baseline assessment developed ADA (83%), the majority (79%) within 3 months. However, anakinra treatment markedly improved symptoms and was effective regardless of the presence of ADA; the annual rates of AEs were comparable between ADA-negative and ADA-positive patients. While ADA are likely to occur in CAPS patients treated with anakinra, our evidence shows that chronic daily subcutaneous treatment with anakinra is safe and effective regardless of the development and presence of ADA.

T cells from human peripheral blood were enriched in T4+ cells by lysis of T8+ cells with the monoclonal antibody OKT8 plus complement. The T4+ subset was separated into 4 fractions differing in avidity for the lectin Helix pomatia A hemagglutinin (HP). The fractions were studied for their capacity to help autologous B cells to differentiate and mature into immunoglobulin (Ig) synthesis and secretion after activation with tetanus toxoid (TT) in vitro. To ensure the antigen specificity of induction, very low doses of TT (1-100 ng/ml) were used for activation of the lymphocytes, all obtained from previously sensitized donors. The T4+ cells with low avidity for HP (fractions HP-I and HP-II) exerted little help for B cell differentiation. Removal of these cells enhanced the helper function of the remaining T4+ cells, indicating that fractions HP-I and HP-II contained suppressor cells. In contrast, efficient B cell help was provided by T4+ cells with high avidity for HP (fractions HP-III and HP-IV). However, these fractions differed in the quality of help provided. Thus, while HP-III cells induced IgG secretion, HP-IV cells mainly induced IgM secretion. Moreover, while the Ig secreted after help from HP-III cells was TT-specific antibody, the Ig secreted by B cells in the presence of autologous HP-IV cells was polyclonal, probably reflecting induction of B cells differing in their responsiveness to signals provided by different types of T cells. The results indicate that T4+ cells vary in their stage of differentiation as seen by differences in expression of the HP marker and that differences in HP-marker expression appear to be associated with differences in cellular functions.