scholarly journals FRI0111 TOCILIZUMAB MAY INDUCE SECONDARY HYPOGAMMAGLOBULINAEMIA. A RETROSPECTIVE CASE SERIES OF 42 PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 636.2-636
Author(s):  
F. Vílchez-Oya ◽  
A. Pros ◽  
I. Carrión Barberà ◽  
J. A. Meraz Ostiz ◽  
T. C. Salman Monte ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
B Cell ◽  
Interleukin 6 ◽  
Human Monoclonal Antibody ◽  
Case Series ◽  
Infection Risk ◽  
Immunoglobulin Levels ◽  
Igg Level

Background:Tocilizumab (TCZ) is a recombinant humanized, anti-human monoclonal antibody of the immunoglobulin G1ksubclass directed against soluble and membrane-bound interleukin 6 receptors (IL-6R) [1].Interleukin-6 (IL-6) has a pleiotropic effect on inflammation, immune response, and hematopoiesis. When it was first identified, it was named as B-cell-stimulating factor 2 (BSF-2) according to its ability to induce immunoglobulin production in Epstein-Barr virus-transformed B-cell lines or in Staphylococcus aureus Cowan 1-stimulated B cells [2-4].Nowadays, it is known that IL-6 controls the survival, population expansion and maturation of B cells and plasmablasts. In that way, the regulation of Blimp-1 by STAT3 is linked to antibody secretion and is associated with long-lived plasma cells that produce large amounts of immunoglobulin. Furthermore, the ability of IL-6 to promote humoral immunity has been linked to its effects on follicular helper T cells where they promote B cell proliferation and immunoglobulin class switching [5].Objectives:Hypogammaglobulinaemia is a known complication of some immunosuppressive drugs, not previously described in patients who received therapy with monoclonal antibody against the IL-6R. We aimed to analyzed the prevalence of hypogammaglobulinaemia in our series of patients treated with tocilizumab after a carefully diagnostic workup which ruled out other causes and analyzed whether is associated with a higher risk of infection.Methods:We conducted a retrospective review from 2010 to 2019 of forty-two patients affected with a rheumatic disease and treated with TCZ at our centre. In those patients in whom we had no record of immunoglobulin levels, we determined them in the blood analysis performed by usual clinical practice.Results:42 patients were identified, from whom 38 had rheumatoid arthritis. A 31% had immunoglobulin levels prior to starting treatment with TCZ but no one had hypogammaglobulinaemia. 2 patients were excluded due to their underlying disease could justify the IgG level abnormalities. During the treatment’s follow-up, we identified that a 30% of the patients (12/40) had hypogammaglobulinaemia. Of those patients in whom immunoglobulin levels had been determined prior to starting treatment with TCZ, a 36.3% of them (4/11) developed hypogammaglobulinaemia during the follow-up. From the series, we observed a statistical significance tendency (p=0.0057) for infection risk in those patients with hypogammaglobulinaemia in contrast to those with normal IgG level (41.5% vs 14.3%, respectively).Conclusion:Secondary hypogammaglobulinaemia may occurs in patients receiving anti-IL6 agents such as tocilizumab and this could be associated with an increasing infection risk. The prevalence is not precisely known, in part because measurement of IgG prior to or during the treatment has not been a standard of care. No medical data have been previously disclosed about this possible adverse effect of anti-interleukin-6 agents. Nevertheless, ideally randomized trials are needed to assess this initial hypothesis.References:[1]Sheppard M, Laskou F, Stapleton PP, Hadavi S, Dasgupta B. Tocilizumab (Actemra). Hum Vaccin Immunother. 2017;13(9):1972–1988.[2]Tanaka T, Kishimoto T. The biology and medical implications of interleukin-6. Cancer Immunol Res. 2014;2(4):288–294.[3]Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295. Published 2014 Sep 4.[4]Kishimoto T. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther. 2006;8 Suppl 2(Suppl 2):S2.[5]Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease [published correction appears in Nat Immunol. 2017 Oct 18;18(11):1271]. Nat Immunol. 2015;16(5):448–457.Disclosure of Interests:Francisco Vílchez-Oya: None declared, Ana Pros: None declared, Irene Carrión Barberà Grant/research support from: I received a grant from the Spanish Rheumatology Foundation (FER) and laboratories KERN PHARMA for a brief stay abroad., Juan Antonio Meraz Ostiz: None declared, Tarek Carlos Salman Monte: None declared, Carolina Perez-Garcia: None declared

scholarly journals Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 435-445 ◽  
Author(s):  
ME Reff ◽  
K Carner ◽  
KS Chambers ◽  
PC Chinn ◽  
JE Leonard ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Chinese Hamster Ovary Cells ◽  
Human Monoclonal Antibody ◽  
B Cell Lymphoma ◽  
Target Cells ◽  
Chimeric Mouse ◽  
Variable Regions

Murine monoclonal antibody 2B8 specifically recognizes the CD20 phosphoprotein expressed on the surface of normal B lymphocytes and B- cell lymphomas. The light- and heavy-chain variable regions of 2B8 were cloned, after amplification by the polymerase chain reaction, into a cDNA expression vector that contained human IgG1 heavy chain and human kappa-light chain constant regions. High-level expression of chimeric- 2B8 antibody (C2B8) was obtained in Chinese hamster ovary cells. Purified C2B8 exhibited antigen binding affinity and human-tissue reactivity similar to the native murine antibody. In vitro studies showed the ability of C2B8 to bind human C1q, mediate complement- dependent cell lysis of human B-lymphoid cell lines, and lyse human target cells through antibody-dependent cellular cytotoxicity. Infusion of macaque cynomolgus monkeys with doses ranging from 1.6 mg/kg to 6.4 mg/kg resulted in greater than 98% depletion of peripheral blood (PB) B cells and 40% to 70% depletion of lymph node B cells. Recovery of PB B cells usually started at 2 weeks after treatment and required 60 to greater than 90 days to reach normal levels. As much as 95% depletion of B cells in peripheral lymph nodes and bone marrow was observed following weekly injections of 16.8 mg/kg antibody. No toxicity was observed in any of the animals. These results offer the possibility of using an “immunologically active” chimeric anti-CD20 antibody as an alternative approach in the treatment of B-cell lymphoma.

scholarly journals Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 435-445 ◽  
Author(s):  
ME Reff ◽  
K Carner ◽  
KS Chambers ◽  
PC Chinn ◽  
JE Leonard ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Chinese Hamster Ovary Cells ◽  
Human Monoclonal Antibody ◽  
B Cell Lymphoma ◽  
Target Cells ◽  
Chimeric Mouse ◽  
Variable Regions

Abstract Murine monoclonal antibody 2B8 specifically recognizes the CD20 phosphoprotein expressed on the surface of normal B lymphocytes and B- cell lymphomas. The light- and heavy-chain variable regions of 2B8 were cloned, after amplification by the polymerase chain reaction, into a cDNA expression vector that contained human IgG1 heavy chain and human kappa-light chain constant regions. High-level expression of chimeric- 2B8 antibody (C2B8) was obtained in Chinese hamster ovary cells. Purified C2B8 exhibited antigen binding affinity and human-tissue reactivity similar to the native murine antibody. In vitro studies showed the ability of C2B8 to bind human C1q, mediate complement- dependent cell lysis of human B-lymphoid cell lines, and lyse human target cells through antibody-dependent cellular cytotoxicity. Infusion of macaque cynomolgus monkeys with doses ranging from 1.6 mg/kg to 6.4 mg/kg resulted in greater than 98% depletion of peripheral blood (PB) B cells and 40% to 70% depletion of lymph node B cells. Recovery of PB B cells usually started at 2 weeks after treatment and required 60 to greater than 90 days to reach normal levels. As much as 95% depletion of B cells in peripheral lymph nodes and bone marrow was observed following weekly injections of 16.8 mg/kg antibody. No toxicity was observed in any of the animals. These results offer the possibility of using an “immunologically active” chimeric anti-CD20 antibody as an alternative approach in the treatment of B-cell lymphoma.

scholarly journals A phase Ib, open-label, dose-escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma

2021 ◽  
Author(s):  
Monica Balzarotti ◽  
Massimo Magagnoli ◽  
Miguel Ángel Canales ◽  
Paolo Corradini ◽  
Carlos Grande ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Human Monoclonal Antibody ◽  
B Cell Lymphoma ◽  
Chimeric Mouse ◽  
Open Label ◽  
Large B Cell Lymphoma ◽  
Large B Cell

SummaryBackground BI 836826 is a chimeric mouse–human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.

scholarly journals Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study

2017 ◽  
Vol 25 (2) ◽  
pp. 235-245 ◽  
Author(s):  
Mark A Agius ◽  
Gabriela Klodowska-Duda ◽  
Maciej Maciejowski ◽  
Andrzej Potemkowski ◽  
Jing Li ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Phase 1 ◽  
B Cell Depletion ◽  
Serious Adverse Events ◽  
T2 Lesions ◽  
Subcutaneous Dose ◽  
Dose Study

Background: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells. Objectives: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. Methods: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL. Results: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively. Conclusion: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.

scholarly journals Lack of mature B cells in nude mice with X-linked immune deficiency.

1982 ◽  
Vol 155 (3) ◽  
pp. 903-913 ◽  
Author(s):  
H H Wortis ◽  
L Burkly ◽  
D Hughes ◽  
S Roschelle ◽  
G Waneck
Keyword(s):  
Immune Deficiency ◽  
B Cells ◽  
B Cell ◽  
Nude Mice ◽  
Normal Serum ◽  
The Other ◽  
Spleen Cells ◽  
Virtual Absence ◽  
Immunoglobulin Levels

Mice were bred that simultaneously expressed the mutations nude and x-linked immune deficiency (xid). These doubly deficient animals had less than 10% of normal serum immunoglobulin levels. Their spleen cells did not respond to thymus-independent antigens in vitro nor did they respond to lipopolysaccharide. There was a virtual absence of cells with surface mu, kappa, or lambda 1, as detected by fluorescence. Sections of lymphoid organs revealed an absence of primary B cell follicles. Taken together, these results indicate a lack of mature B cells in nude xid mice. The possibility is considered that mature B cells belong to two subpopulations representing two lineages, one controlled by alleles at the xid locus and the other by alleles at the nude locus.

scholarly journals Selective inhibition of growth factor-dependent human B cell proliferation by monoclonal antibody AB1 to an antigen expressed by activated B cells.

1984 ◽  
Vol 160 (6) ◽  
pp. 1919-1924 ◽  
Author(s):  
L K Jung ◽  
S M Fu
Keyword(s):  
Monoclonal Antibody ◽  
Cell Proliferation ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Leukemic Cells ◽  
Activated T Cells ◽  
Igm Antibodies ◽  
Stimulatory Factor ◽  
Activated B Cells

A monoclonal antibody, AB1, was established with activated human B cells as immunogen. AB1 stained activated B cells but not activated T cells. Its selective reactivity to activated B cells was further documented by its nonreactivity to activated T cells, resting T and B cells, monocytes, granulocytes, bone marrow cells, leukemic cells, and cells from cell lines of T, B, and myeloid lineages. Upon activation, the antigen appeared on B cells as early as 3-4 h after stimulation and was fully expressed by 38 h. The expression of this antigen was not dependent on the presence of B cell stimulatory factor(s). Anti-IgM antibodies by themselves induced its expression. AB1 inhibited B cell proliferation that was induced by a low dose anti-IgM antibody and conditioned medium containing B cell stimulatory factor. It did not inhibit B cell proliferation induced by either high doses of anti-IgM antibodies or by formalinized Staphylococcus aureus. It also failed to inhibit T cell mitogenesis. The possibility exists that this antigen is related to the receptor for B cell stimulatory factor.

scholarly journals Tocilizumab in the treatment of severe and refractory parenchymal neuro-Behçet’s syndrome: case series and literature review

2020 ◽  
Vol 12 ◽  
pp. 1759720X2097190
Author(s):  
Jinjing Liu ◽  
Dong Yan ◽  
Zhimian Wang ◽  
Yunjiao Yang ◽  
Shangzhu Zhang ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Interleukin 6 ◽  
Case Series ◽  
Interquartile Range ◽  
Behçet’S Syndrome ◽  
Serious Adverse Events ◽  
Behçet's Syndrome ◽  
Behcet’S Syndrome ◽  
Behcet's Syndrome

Objectives: This study aimed to investigate the efficacy and safety of tocilizumab (TCZ) in severe and refractory parenchymal neuro-Behçet’s syndrome (p-NBS). Methods: We retrospectively analyzed five patients with p-NBS treated with TCZ in our center between 2013 and 2020, and six cases from literature research with the index terms “neuro-Behçet’s syndrome” and “tocilizumab” on PubMed NCBI. Results: A total of 11 patients with p-NBS were enrolled (5 males, 6 females), with a mean age of 34.5 ± 8.0 years at the onset. All the patients had parenchymal neurological lesions, six patients (54.5%) suffered from multiple lesions, and nine patients (81.8%) were disabled. Before TCZ administration, all the patients had failed conventional therapy, eight patients (72.7%) received two or more immunosuppressants, and five patients showed insufficient response or intolerance to other biologics. TCZ was administrated at 8 mg/kg every 4 weeks, with background glucocorticoids (GCs) and immunosuppressants. After a median follow-up of 13 (interquartile range, 3.5–23.5) months, all the patients achieved both clinical and radiological improvements, and the Behçet’s Disease Current Activity Form score improved significantly (3 versus 0, median, p = 0.004), the Rankin score also decreased (4 versus 2, median, p = 0.005). Levels of interleukin-6 in the cerebrospinal fluid decreased significantly in five patients (533.4 ± 389.7 pg/ml versus 34.5 ± 27.1 pg/ml, p = 0.048), after a median of two (interquartile range, 1–4) times of TCZ infusions. Furthermore, the GC dosage ( per os) reduced from 69.2 ± 16.9 mg/d to 16.4 ± 16.2 mg/d ( p = 0.000), and immunosuppressants were tapered in number and dosage in seven (63.6%) and four (36.3%) patients, respectively. No serious adverse events or deaths were observed during follow-up. Conclusions: TCZ is well tolerated and effective in severe and refractory p-NBS, with a favorable GC- and immunosuppressant-sparing effect. Cerebrospinal fluid interleukin-6 might be used to monitor the effects of TCZ in p-NBS.

Tumor Targeting, Dosimetry and Clinical Response Data for Lymphorad-131 (LR131; Iodine I-131 Labeled B-Lymphocyte Stimulator) in Patients with Relapsed/Refractory Non-Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 750-750 ◽  
Author(s):  
Andrew Belch ◽  
Alexander McEwan* ◽  
Joanne Hewitt* ◽  
Terence Riauka ◽  
Michael Stabin* ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Pet Imaging ◽  
Hodgkin’S Lymphoma ◽  
B Lymphocyte ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
B Lymphocyte Stimulator

Abstract LR131 is a novel radioconjugate consisting of B Lymphocyte Stimulator (BLyS) protein, a B cell maturation factor of the TNF family that binds selectively to immunoglobulin-positive B cells, labeled with Iodine I 131. BLyS receptors are present on normal B cells and B cell malignancies. Ten subjects with relapsed, refractory follicular non-Hodgkin’s lymphoma (8M/2F, age 33–61) have been entered on study at the Cross Cancer Institute as part of a multicenter phase 1 dose escalation trial. FDG-PET and CT imaging were performed prior to and following LR131 therapy to evaluate tumor response and recurrence. Previous therapies for these patients included single and multiagent chemotherapy, limited field external beam radiation therapy and Rituximab with/without concomitant chemotherapy. Patients had an average of 2.6 previous therapies (range 1–4). Patients received an imaging/dosimetry dose of 5–7 mCi of LR131 followed 1–2 weeks later by the therapeutic dose. CT and PET confirmed specific tumor localization in all patients. Ten of ten patients targeted sites of disease seen on CT and PET with LR131 although one patient with rapidly progressing end stage disease did not uniformly target a very large tumor mass in the abdomen/pelvis. Administered activities for therapy were 0.35 mCi/kg (10 m g/kg BLyS), 0.70 mCi/kg (30 m g/kg BLyS), 1.35 mCi/kg (75 m g/kg BLyS) and 1.70 mCi/kg (75 m g/kg BLyS) for the first four cohorts, respectively. Of 8 evaluable patients through at least 12 weeks of follow-up there were 2 CRu, 2 PR and 1 SD. In the two patients with CRu, follow-up PET scanning was negative for FDG accumulation in all areas of previous activity. One patient had significantly decreased activity on PET (4 weeks) later confirmed as PR by CT. Two patients have been retreated including one CRu (1 year) who showed renewed positive activity on PET imaging (negative CT) which returned to negative following retreatment and 1 PR. There have been no dose limiting toxicities seen to date on initial or retreatment. Time activity curves were generated after drawing ROIs and analyzed with SAAM II. Doses were calculated using MIRDOSE 3.1 (Stabin 1996). Deposited doses to critical organs were 0.48, 0.55, 2.13, 0.49, 0.37 cGy/mCi to the liver, lung, kidney, marrow and total body, respectively, and were significantly lower than those seen with the approved iodine labeled anti-CD20 monoclonal antibody (3.03, 2.92, 7.25, 2.41, 0.89 cGy/mCi for the same organs). LR131 demonstrated rapid clearance from blood and normal organs with retained activity in sites of tumor. Tumor deposited doses ranged from 45 cGy in the patient that did not target to 3600 cGy. CONCLUSION: LR131, at the administered doses studied to date, has been well tolerated with only mild to moderate reversible toxicity. LR131 has demonstrated targeting and clinical efficacy that has correlated with CT and PET imaging

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