Reduction In IgG Levels Research Articles

Efgartigimod Successfully Ameliorated Acute Exacerbation of Myasthenia Gravis with Anti-muscle-specific Kinase Antibodies.

We herein report two patients with anti-muscle-specific kinase (MuSK) antibody-positive myasthenia gravis who experienced rapid deterioration of weakness, particularly respiratory muscle weakness, necessitating non-invasive positive pressure ventilation (NIPPV) and were treated with efgartigimod. After treatment initiation, a rapid reduction in IgG levels and recovery from clinical symptoms were observed. NIPPV was no longer required two to three weeks after the first infusion of efgartigimod. These findings suggest that the reduction of IgG levels using efgartigimod is a good treatment option in patients with myasthenia gravis positive for anti-MuSK antibodies, even during the acute phase of the disease.

P.034 Minimal symptom expression following treatment with efgartigimod in patients with Generalized Myasthenia Gravis

Background: Efgartigimod is a human IgG1 antibody Fc-fragment that reduces IgG levels through FcRn blockade. A key efficacy indicator in the treatment of IgG autoantibody-mediated generalized myasthenia gravis (gMG) is improvement in MG-ADL score. Methods: The ADAPT phase 3 trial evaluated safety and efficacy of efgartigimod in patients with gMG, including reaching and maintaining of minimal symptom expression (MSE; defined as an MG-ADL total score of 0 or 1). Results: 167 patients (AChR-Ab+, n=129; AChR-Ab-, n=38) were randomized to receive treatment cycles of 4 weekly infusions of efgartigimod or placebo. Significantly more AChR-Ab+ efgartigimod-treated patients achieved MSE during cycle 1 compared to placebo-treated patients (40.0% [n=26/65] vs 11.1% [n=7/63; P<0.0001]). In cycle 2, 31.4% (n=16/51) of AChR-Ab+ patients in the efgartigimod cohort achieved MSE compared to none in the placebo cohort. MG-ADL score improved by ≥6 points in 56.9% of AChR-Ab+ efgartigimod-treated patients compared to 20.6% of placebo-treated patients in cycle 1. Most patients achieved MSE by week 4 of a cycle, paralleling early reduction in IgG levels, and MSE duration ranged from 1 to ≥10 weeks. Adverse events were predominantly mild to moderate. Conclusions: Efgartigimod treatment resulted in more patients with AChR-Ab+ gMG achieving both MSE and clinically meaningful MG-ADL improvements.

Kinetics of T-Cell Subset Reconstitution Following Bendamustine-Containing Therapy for Low-Grade Lymphoproliferative Disease; A Population Based Analysis

BackgroundThe efficacy of Bendamustine and Rituximab (BR) for indolent NHL (iNHL) has been demonstrated in 2 randomised studies (StiL NHL1 and BRIGHT), although combination therapy with monoclonal antibodies remains an off-label use. Increased toxicity was apparent in both bendamustine cohorts of the GALLIUM study, with 5% treatment-related mortality (TRM) versus 1.8% in the CHOP/CVP arms. Recently, the UK MHRA (Medicines and Healthcare products Regulatory Agency) issued notification of increased infection risks in the context of bendamustine combination therapy. Given these concerns we undertook an observational analysis of T-cell reconstitution and mortality following Bendamustine-based therapy within a large University hospital.MethodsPatients who received bendamustine for CLL or lymphoma between April 2012-Jan 2017 were identified from our electronic prescribing database. We evaluated clinical outcomes following treatment, and assessed absolute lymphocyte count (ALC), CD4, CD8, NK-cells and immunoglobulin levels over time.Results173 patients were identified, 171 (99%) received bendamustine combination therapy, 2 (1%) received monotherapy. The median age was 68 years (range 34-93). 71% had iNHL (follicular n=63, marginal zone n=34, LPL n=25), 22% had CLL whilst mantle, DLBCL and Hodgkin lymphoma accounted for 7% (n=13). The median number of previous therapy lines was 1 (0-7). Excluding CLL and overt leukaemic disease (32% of the cohort), the median ALC pre-bendamustine was 1.3x109/l (0.2-3.9x109/l) with a median nadir at 1 month post treatment of 0.5x109/l. After 12 months, 77% of this cohort had an ALC of ≥ 0.5 x109/l and 28% an ALC of ≥ 1.0 x109/l . 82 patients (47%) had immunoglobulin levels assessed within 3-12 months of bendamustine with a median IgG level of 5.2g/l (range 2-14.3). Of these 38 (46%) were <5g/l, and 15 (18%) were <3g/l.Given the potential unreliability of ALC in the context of iNHL and CLL and to better inform duration of antimicrobial prophylaxis, we evaluated T- lymphocyte recovery in more detail. Of the whole cohort, 27% (n=47) had undergone a full lymphocyte subset analysis by flow cytometry at least once following bendamustine-based treatment. The median number of lymphocyte subset analyses evaluated per patient was two (range 1-5) at time-points ranging from 1-40 months post-bendamustine.The median CD4 count in the first 6 months post bendamustine was 0.117 x109/L. 30 patients (65%) had at least one CD4 count <0.200 x109/L (200/ul), and these patients had an initial median CD4 count of 0.085 x109/L. We observed a marked delay in CD4 recovery for the whole cohort and those with initial post treatment CD4 count <0.200 x109/L, with median CD4 counts at 24 months of 0.198 x109/L and 0.124 x109/L respectively (table 1). NK-cell numbers on the same follow-up samples were also depleted, with 21% initially below the lower limit of normal, and although less profound reductions in absolute numbers were seen, recovery followed similar kinetics to CD4 cells. Interestingly, median CD8 counts were within normal range in the first 6 months post bendamustine treatment, with no clear change in absolute numbers over time (figure 1).For the whole cohort, 31 deaths were observed (18%), 11 due to progressive disease. Of the 20 non-lymphoma-related deaths, 10 were due to infection but only 4 (13%) occurred within 6 months of bendamustine. Of the remaining 6 deaths, all had received at least 1 subsequent line of treatment (including stem cell transplant in 3 cases). Of the remaining 10, 4 occurred within 12 months of bendamustine and were attributed to lung fibrosis, glioblastoma, gastric cancer and pulmonary embolism.ConclusionAmongst a population-based cohort of bendamustine-treated patients, we have demonstrated slow kinetics of T-cell reconstitution. The majority of patients experienced marked CD4 lymphopenia, with most failing to reconstitute >0.200 x109/L by 24 months post therapy. Similar but less profound reductions were seen in NK-cell numbers in addition to clinically significant reductions in IgG levels. Importantly, ALC did not correlate with the CD4 numbers and is unlikely to be a reliable indicator of T-cell recovery. These data may, at least in part, explain the TRM of bendamustine-based therapy and supports extended duration of antimicrobial prophylaxis against opportunistic infection, informed by CD4 recovery. [Display omitted] DisclosuresMcMillan:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel sponsorship. Bishton:Roche: Other: Travel Sponsorship. Fox:AbbVie: Consultancy, Honoraria, Other: Travel Sponsorship, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Sponsorship, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Sponsorship, Speakers Bureau.

Compare the epidemiological and clinical features of imported and local COVID-19 cases in Hainan, China

BackgroundEffective management of imported cases is an important part of epidemic prevention and control. Hainan Province, China reported 168 coronavirus disease 2019 (COVID-19), including 112 imported cases on February 19, 2020, but successfully contained the epidemic within 1 month. We described the epidemiological and clinical characteristics of COVID-19 in Hainan and compared these features between imported and local cases to provide information for other international epidemic areas.MethodsWe included 91 patients (56 imported and 35 local cases) from two designated hospitals for COVID-19 in Haikou, China, from January 20 to February 19, 2020. Data on the demographic, epidemiological, clinical and laboratory characteristics were extracted from medical records. Patients were followed until April 21, 2020, and the levels of antibodies at the follow-ups were also analysed by the Wilcoxon matched-pairs signed ranks test.ResultsOf the 91 patients, 78 (85.7%) patients were diagnosed within the first three weeks after the first case was identified (Day 1: Jan 22, 2020), while the number of local cases started to increase during the third week. No new cases occurred after Day 29. Fever and cough were two main clinical manifestations. In total, 15 (16.5%) patients were severe, 14 (15.4%) had complicated infections, nine (9.9%) were admitted to the intensive care unit, and three died. The median duration of viral shedding in feces was longer than that in nasopharyngeal swabs (19 days vs 16 days, P = 0.007). Compared with local cases, imported cases were older and had a higher incidence of fever and concurrent infections. There was no difference in outcomes between the two groups. IgG was positive in 92.8% patients (77/83) in the follow-up at week 2 after discharge, while 88.4% patients (38/43) had a reduction in IgG levels in the follow-up at week 4 after discharge, and the median level was lower than that in the follow-up at week 2 (10.95 S/Cut Off (S/CO) vs 15.02 S/CO, P < 0.001).ConclusionImported cases were more severe than local cases but had similar prognoses. The level of IgG antibodies declined from week 6 to week 8 after onset. The short epidemic period in Hainan suggests that the epidemic could be quickly brought under control if proper timely measures were taken.

Acquired hypogammaglobulinemia and pathogen-specific antibody depletion after solid organ transplantation in human immunodeficiency virus infection: A brief report.

Hypogammaglobulinemia (HGG) frequently occurs in recipients after types of (SOT). The incidence and significance of HGG in HIV+recipients of SOT are just being explored. We reported that 12% of the recipients in the SOT in multi-center HIV-TR (HIV-TR) Study developed moderate or severe HGG at 1year. In LT recipients, this was associated with serious infections and death. We have now further characterized the decreased antibodies in HIV+SOT recipients who developed HGG. We measured the levels of pathogen-specific antibodies and poly-specific self-reactive antibodies (PSA) in relation to total IgG levels from serial serum samples for 20 HIV+SOT recipients who developed moderate to severe HGG following SOT. Serum antibody levels to measles, tetanus toxoid, and HIV-1 were determined by EIA. Levels of PSAs were determined by incubating control lymphocytes with patient serum, staining with anti-human IgG Fab-FITC, and analysis by flow cytometry. Levels of PSA were higher compared to healthy, HIV-uninfected controls at pre-transplant baseline and increased by weeks 12 and 26, but the changes were not significant. Likewise, anti-HIV antibody levels remained unchanged over time. In contrast, antibody levels against measles and tetanus were significantly reduced from baseline by week 12, and did not return to baseline, even after 2years. For HIV patients who develop moderate to severe HGG after transplant, the reduction in IgG levels is associated with a significant decrease in pathogen-specific antibody titers, while PSA levels and anti-HIV antibodies are unchanged. This may contribute to infectious complications and other clinical endpoints.

Fully human monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates.

The therapeutic management of antibody-mediated autoimmune disease typically involves immunosuppressant and immunomodulatory strategies. However, perturbing the fundamental role of the neonatal Fc receptor (FcRn) in salvaging IgG from lysosomal degradation provides a novel approach – depleting the body of pathogenic immunoglobulin by preventing IgG binding to FcRn and thereby increasing the rate of IgG catabolism. Herein, we describe the discovery and preclinical evaluation of fully human monoclonal IgG antibody inhibitors of FcRn. Using phage display, we identified several potent inhibitors of human-FcRn in which binding to FcRn is pH-independent, with over 1000-fold higher affinity for human-FcRn than human IgG-Fc at pH 7.4. FcRn antagonism in vivo using a human-FcRn knock-in transgenic mouse model caused enhanced catabolism of exogenously administered human IgG. In non-human primates, we observed reductions in endogenous circulating IgG of >60% with no changes in albumin, IgM, or IgA. FcRn antagonism did not disrupt the ability of non-human primates to mount IgM/IgG primary and secondary immune responses. Interestingly, the therapeutic anti-FcRn antibodies had a short serum half-life but caused a prolonged reduction in IgG levels. This may be explained by the high affinity of the antibodies to FcRn at both acidic and neutral pH. These results provide important preclinical proof of concept data in support of FcRn antagonism as a novel approach to the treatment of antibody-mediated autoimmune diseases.

AB0519 Auto-antibody titers for monitoring rituximab therapy in rheumatoid arthritis

BackgroundMonitoring auto-antibody titers has been suggested as a means of assessing treatment efficacy in rheumatoid arthritis (RA) patients. Several studies evaluated the effect of anti-TNF antagonist treatment on auto-antibody titers...

Anti-Myeloma Effects of Carfilzomib with Cyclophosphamide (CY) or Bendamustine (Ben).

Abstract 2952 Introduction:Carfilzomib (Onyx Pharmaceuticals, South San Francisco, CA, USA) is an irreversible proteasome inhibitor (PI) that has shown preclinical and clinical efficacy against multiple myeloma (MM). It has shown clinical benefit as a single agent and with steroids in early clinical trials, even among patients resistant to prior bortezomib treatment. We determined the anti-MM effects of carfilzomib in combination with cyclophosphamide (CY) or bendamustine (Ben) in vivo using our xenograft model of human MM, LAGk-1A. Methods:Each SCID mouse received a 20 – 40 mm3 MM tumor piece surgically implanted into the hind limb. Seven days post-implantation mice were bled, human IgG levels were measured by ELISA and mice randomized into groups. Carfilzomib stock solution (2 mg/ml) was diluted to 3 mg/kg using 10% capsitol and administered twice weekly via intravenous (i.v.) injection. Cyclophosphamide (Baxter, Deerfield, IL, USA) stock solution (20 mg/ml) was diluted in sodium chloride and administered via oral gavage once weekly at 10 mg/kg. Bendamustine (Teva Pharmaceuticals, North Wales, PA, USA) stock solution (5 mg/ml) was diluted to 5 mg/kg in sterile water and administered via intraperitoneal (i.p.) once weekly. Mice (n = 8) were bled to determine hIgG levels and the tumors were measured using standard calipers. Data was analyzed as the mean ± SEM. Results:LAGk-1A-bearing mice treated with single agent carfilzomib or CY did not show a reduction in tumor growth compared to vehicle-treated mice. In contrast, the combination of carfilzomib plus CY resulted in a statistically significant decrease in tumor size and IgG levels when compared to vehicle-treated mice on days 35, 42, 49, and 56 (tumor volume; P = 0.0007, P = 0.0003, P = 0.0008 and P = 0.0001: IgG levels; P = 0.0023, P = 0.0327, P = 0.0219 and P = 0.0190, respectively). Toxicity was minimal as seven of eight mice survived this combination regimen. Furthermore, tumor growth delay (TGD) to a volume of 1,125 mm3 was delayed by 53.6% (22 days, day 41 for control compared to day 63 for the carfilzomib + CY group) among animals receiving this combination treatment regimen when compared to vehicle-treated animals. In contrast, shorter TGDs were obtained when mice were dosed with single agents. When mice were dosed with carfilzomib alone, a TGD of 12.1% (5 days, day 41 for control compared to day 46 for the carfilzomib group) was obtained. When mice were dosed with CY alone, a TGD of 26.8% (11 days, day 41 for control compared to day 52 for the CY group) was obtained. Percentage inhibition of tumor growth (T/C) is represented as the median tumor volume of the test drug group over the median tumor volume of the vehicle group. A T/C ratio of ≤42% is indicative of drug efficacy. At day 56 post tumor implantation, mice receiving single agent treatment with carfilzomib or CY had T/C’s of 88% and 67%, respectively. In contrast, at the same time point, mice receiving the cafilzomib plus CY regimen resulted in a lower percentage T/C of 29%. We also evaluated the combination of carfilzomib plus Ben in LAGk-1A-bearing mice. Animals treated with single agents did not result in a reduction in tumor volume compared to vehicle-treated mice. In contrast, the combination of carflzomib and Ben resulted in a decrease in tumor size compared to vehicle-treated mice on days 35, 42, 49, and 56 (P = 0.0184, P < 0.0001, P = 0.0035, and P = 0.0026, respectively). Additionally, this combination resulted in a reduction in IgG levels compared to vehicle-treated mice on days 42, 49 and 56 (P = 0.0426, P = 0.0257 and P = 0.0204, respectively). Furthermore, six of eight mice survived this treatment regimen. Compared to vehicle-treated mice, animals treated with the combination treatment showed a TGD to 1,250 mm3 of 38% (16 days, day 42 for control compared to day 58 for the carfilzomib + Ben). When compared to vehicle-treated mice, carfilzomib-treated animals showed a TGD of only 14.3% (6 days, day 42 for control compared to day 48 for the carfilzomib), and there was no TGD for mice treated with Ben alone. Conclusions:We have shown that the combination of carfilzomib plus CY or Ben shows marked anti-MM effects using our xenograft MM model LAGk-1A. The results from these preclinical studies provide the basis for clinical trials evaluating the combination of carfilzomib with CY or Ben for patients with MM. Disclosures:Berenson:Onyx: Consultancy, Honoraria, Speakers Bureau.

The G-Immunoglobulins in Acute Leukemia in Children Hematologic and Immunologic Relationships

Abstract Serial IgG determinations were carried out on 29 children with acute leukemia. With the exception of the pretreatment assays, all determinations were performed during the course of specific antileukemic therapy. Following the initial introduction to cytotoxic agents, a significant, although temporary, reduction in IgG level occurred. The continuous use of antileukemic agents did not alter the IgG levels. Relapses, responsive to changes in therapy, were usually associated with moderate reductions in the IgG levels. Greater reductions in IgG levels occurred following the institution of changes in therapy. In both instances the declines were followed by a return in IgG to the normal range. Declines of significantly greater magnitude and rate occurred in those patients no longer capable of responding to therapy changes. In such patients, levels below 3.8 to 3.5 mg./ml. signified impending death, a lack of response to infection and inability to evoke an IgG response. An example of the interrelationships between clinical and immunologic responsiveness is shown by the patient in complete relapse with a normal IgG assay, who went into remission and had an impressive IgG response following a rubeola infection. Shortly thereafter, her disease process entered an irreversible relapse stage with an IgG level of 2.9 mg./ml., and death occurred within 30 days following a bacterial septicemia. The relationship between hematologic and immunologic responsiveness raises the provocative question of paradoxically maintaining an immunologically responsive state as a means of prolonging the survival time in the face of persistent immunosuppressive therapy.