scholarly journals P54 Pneumocystis jirovecii prophylaxis in patients on rituximab

Rheumatology ◽  
2019 ◽  
Vol 58 (Supplement_4) ◽  
Author(s):  
Kishore Warrier1 ◽  
Catherine Salvesani ◽  
Samundeeswari Deepak
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Pneumocystis Jirovecii ◽  
Current Evidence ◽  
Pneumocystis Jirovecii Pneumonia ◽  
Number Of Patients ◽  
Increased Risk

Abstract Background Rituximab is a chimeric monoclonal antibody that depletes the B cell population by targeting cells bearing the CD20 surface marker and is used widely in the management of paediatric rheumatological conditions like juvenile systemic lupus erythematosus (JSLE), juvenile dermatomyositis (JDM), mixed connective tissue disease (MCTD) and juvenile idiopathic arthritis (JIA). Pneumocystis jirovecii pneumonia (PCP) is a potentially fatal opportunistic infection associated with congenital and acquired defects in T cell–mediated immunity. Our guideline did not recommend prophylaxis against PCP for patients on rituximab, unlike patients on cyclophosphamide, who are on cotrimoxazole until three months after cessation of the treatment. Cyclophosphamide is an alkylating agent which affects both B and T lymphocytes. Following the death of 16 year-old girl with JSLE due to PCP, the team reviewed the possible contributing factors, undertook a review of literature and discussed this at multi-disciplinary meetings involving the microbiology and immunology teams. This patient was found to have other risk factors for PCP – low CD4 T cells, concomitant use of corticosteroids and hypogammaglobulinaemia (IgG 3.0g/L). Although there is limited evidence that rituximab on its own increases the risk of PCP, there is emerging data that B cells may have a role in the protection against pneumocystis. Following the review, it was concluded that children on rituximab and an additional immunosuppressant (including corticosteroids) should receive prophylactic cotrimoxazole to cover PCP. Methods Retrospective audit carried out by the team to look at adherence to the new guideline regarding the use of cotrimoxazole for PCP prophylaxis in patients who have had rituximab between August 2017 and May 2019. Results P54 Table 1 Total number of patients who had rituximab 10 Number of patients who had other immunosuppressants concomitantly / recently (within previous 3 months) 7 Number of patients on rituximab monotherapy 2 Number of patients who are 6 months post-treatment 1 Number of patients with other risk factors for PCP 1 (hypogammaglobulinaemia) Number of patients who are eligible for prophylaxis, as per the guideline 8 (7 for concomitant immunosuppression and 1 for hypogammaglobulinaemia) Number of patients on cotrimoxazole 7 (87.5%) - one of the patients is on methotrexate, which is advised not to combine with cotrimoxazole We achieved 87.5% compliance in prescribing cotrimoxazole for PCP prophylaxis to all rheumatology patients receiving rituximab alongside another immunosuppressant agent; the one patient who this was not adhered to was due to potential adverse drug pharmacodynamic interaction between cotrimoxazole and methotrexate. Conclusion Although the current evidence points to increased risk of PCP in patients with inherited and iatrogenic defect of T cell function, there is emerging evidence that B cells may have a role too. Hence more work is required to determine the risk of PCP in patients on B cell targeted therapy (BCTT) and the need for prophylaxis. Conflicts of Interest The authors declare no conflicts of interest.

ICOS Gene Polymorphisms In B-Cell Chronic Lymphocytic Leukemia In a Polish Population.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4614-4614 ◽  
Author(s):  
Irena Frydecka ◽  
Lidia Karabon ◽  
Anna Jedynak ◽  
Anna Tomkiewicz ◽  
Edyta Pawlak ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Costimulatory Molecule ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
Polish Population ◽  
Increased Risk ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abstract 4614 Introduction: There is strong evidence that altered immunological function entails an increased risk of B-cell chronic lymphocytic leukemia (B-CLL). The main mechanism of an antitumor response depends on T-cell activation. Unlike the constitutively expressed CD28, inducible costimulatory molecule (ICOS) is expressed on the T-cell surface after activation. ICOS enhances all the basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, the up-regulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B cells. ICOS is essential for both efficient interaction between T and B cells and normal antibody responses to T cell-dependent antigens. It does not up-regulate the production of interleukin-2, but superinduces the synthesis of interleukin-10. Our previous results indicated a role of ICOS gene as a susceptibility locus to B-CLL. Therefore an extended study was undertaken to evaluate the association between four ICOS polymorphisms (which were recently described as functional ones) and susceptibility to B-CLL in a Polish population. Methods: A case-control study of 296 individuals including 146 B-CLL patients was conducted on four polymorphisms in the ICOS gene. Genotyping of the polymorphisms ICOSISV1+173T>C (rs10932029), ICOSc.1624C>T (rs10932037), ICOSc.2373G>C (rs4675379), and ICOSc.602A>C (rs10183087) was done using allelic discrimination methods with the TaqManÒ SNP Genotyping Assay. Results: There were no statistically significant differences in the allele, genotype, and haplotype distributions between B-CLL patients and healthy controls for any of the investigated polymorphic markers in the ICOS gene. However, we noted that patients carrying genotype ISV1+173T>C [TT], ICOSc.602A>C [AA], ICOSc.1624C>T [CC], and ICOSc.2373G>C [GG] have a decreased frequency of progression to a higher Rai stage during 60-month follow-up (21.35 vs. 40.8%, p=0.013) compared with other individuals. Conclusion: This study showed that the investigated polymorphisms do not modulate the risk of B-CLL in the Polish population, but are associated with disease dynamics in particular with the time to Rai stage progression. Disclosures: No relevant conflicts of interest to declare.

Occurence of Malignancies in Patients with Primary Immunodeficiencies: An Analysis of the French Primary Immunodeficency Registry

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1057-1057
Author(s):  
Felipe Suarez ◽  
Hugo Chapdelaine ◽  
Laetitia Compain ◽  
Nizar Mahlaoui ◽  
Chantal Andriamanga ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Solid Tumors ◽  
Conflicts Of Interest ◽  
Primary Immunodeficiencies ◽  
Age At Diagnosis ◽  
Low Grade ◽  
Lymphoid Malignancies ◽  
Younger Age ◽  
Increased Risk

Abstract Abstract 1057 Background: Primary immunodeficiencies (PID) are rare congenital disorders involving defects of the immune system. Aside from infectious complications, patients are at increased risk of malignant complications, which represent a leading cause of mortality in this context. The pathophysiology underlying malignant complications, especially lymphoid malignancies, in PID is not fully understood. The molecular mechansims of PID, that often involve lymphoid developent pathways, may also play a role in oncogenesis. A better understanding of the epidemiology of malignancies in PID may provide important insights in oncogenesis, particularly in lympomagenesis. Material and methods: French National Reference Center for Primary Immune Deficiencies (CEREDIH) has registered 4632 patients with PID as of July 2012. T-cell immunoficiencies and B-cell immodificencies reprensent 35.8% and 46.1% respectively. Patients with Ataxia-Telangiectasia and Severe Congenital Neutropenia were excluded frome the present analysis as they represent a more homogeneous group in terms of molecular pathophysiology and have been described elsewhere. T-cell immunodeficiencies comprise Severe combined immudoficiencies, Combined immunodeficiencies, other well defined T-cell immunoficiencies (including Wiskott-Aldrich Syndrome), and diseases of immune regulation (including X-linked lymphoproliferative disease and Autoimmune lymphoproliferative syndrome). B-cell immunodeficiencies include Agammaglobulinemia, Common Variable Immunodeficiency, Unspecified primary hypogammaglobulinemia, Selective IgA deficiency, Hyper-IgM symdrome and IgG subclass deficiency. Diagnostic class of PID, Age at diagnosis of PID, age at diagnosis of neoplastic complication, type of neoplasia, and survival were retrospectively colloected from the medical files. Non-melanomatous skin cancers and lymphoproliferative disorders occuring after allogeneic stem cell tranplantation were excluded from the analysis. Results: 4632 patients with PID were analyzed. Two hundred and sixty seven patients developed 276 cancers (incidence 5.8%). One hundred and fifty seven patients developed lymphoid malignancies and 78 patients developed solid tumors (56.4% vs. 28.3% respectively). Compared to patients with B-cell PID, patients with T-cell PID had lower age at diagnosis of PID (5.5 [0–12.4] vs. 1.3–78]). Lymphoid malignancies, mainly high grade lymphomas were more prevalent in T-cell PID and PID diagnosed at a younger age (median age at diagnosis of PID for patients with lymphoid malignancies vs. solid tumors, 5.2 yr [0–85] and 37.5 [0–80] respectively, p<0,001). More than 75% of solid tumors occured in patients with B-cell PID with a median age of 45 yr. at diagnosis of cancer (p<0,001 compared to lymphoid malignancies for the entire cohort). Occurence of lymphoid malignancies had a major impact on mortality in patients with PID, with an overall survival (OS) of 24.7 yr [0.2–86] vs. 58.3 yr [0.2–90.8] for patients with solid tumors (p<0,001). The difference in OS between PID patients developing solid tumors was not statistically different than the whole cohort of PID patients. Both high and low-grade lymphomas were observed in patients with PID developing lymphoid malginancies. The majority of low grade-malignancies were oberserved in patients with B-cell PID. Discussion: PID bear a high risk of malignancies (5.8%). Solid tumors are observed mainly in B-cell PID and are diagnosed at an older age. Lymphoid malignancies are observed mainly in T-cell PID and B-cell PID diagnosed at a younger age, underlying a possible pathophysiological link between T-cell PID and a subset of B-cell PID. Disclosures: No relevant conflicts of interest to declare.

Malignant Lymphoma and Breast Implants: a Case of Diffuse Large B-Cell Lymphoma (DLBCL) with Implant-near Relapse Localization

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5103-5103 ◽  
Author(s):  
Maja Ølholm Vase ◽  
Elisa Jacobsen Pulczynski ◽  
Knud Bendix ◽  
d'Amore Francesco
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Breast Implants ◽  
B Cell Lymphoma ◽  
Thoracic Wall ◽  
High Dose ◽  
Increased Risk

Abstract Abstract 5103 An increased risk of alk-negative T-cell derived anaplastic large-cell lymphoma (T-ALCL) in patients with breast prostheses has been suggested, although unequivocal evidence of an association has not yet been provided. Several reports have also suggested that silicone, one of the major components of breast prostheses, activates the immune system, and induction of myeloma has been shown in a murine model. While association to breast prostheses has been described in as many as 48 patients with T-cell derived ALCL1, only one case of breast implant-associated B-cell derived lymphoma, displaying a follicular histology2, has been reported so far. We here present a case of DLBCL diagnosed in 2006 in a 66 year-old woman, who had undergone cosmetic implantation of bilateral breast prostheses 20 years previously. The disease initially involved right cervical and mediastinal nodes. She was treated with chemo-immunotherapy (rituximab + CHOP q 3 weeks for a total of 8 series) achieving a complete remission (CR) by summer 2006. Almost 1 year later, a nodal DLBCL relapse occurred at cervical level. The patient was again treated with chemoimmunotherapy (rituximab+ dexamethasone, high-dose cytosine arabinoside and cis-platin q 3 weeks for a total of 3 series). A new CR was obtained and consolidated with an autologous transplant with BEAM conditioning in March 2008. More than a year later, a new cervical node relapse occurred along with a small focus in the lung (not bioptically verified). From then on, the patient received multiple therapies, every time with initial chemosensitivity, but quickly followed by new progression as soon as therapy was discontinued. According to PET assessment, there has never been any tumour manifestation below the diaphragm, and no lymphoma infiltration was detected at any time in the bone marrow. As of June 2010, the patient developed multiple cutaneous and subcutaneous tumours corresponding to the anterior thoracic wall in close proximity to the upper quadrants of both breasts. These tumors were preceeded by an erythematous lesion clearly demarcating the cutaneous area of the anterior thoracic wall and breasts corresponding to the underlying implants. Cutaneous biopsies taken at this erythematous stage already revealed diffuse DLBCL infiltration of the skin and subcutis. Cutaneous and subcutaneous biopsies showed alk-negative, CD30-negative CD20-positive DLBCL. All previous lymph node biopsies are CD20 positive, bcl-2 and bcl-6 positive and negative for CD10. A fraction of tumour cells expressed MUM-1. By and large, no major changes in the immunohistochemical profile of the tumor have been observed since the original diagnosis in 2006. The striking anatomical localization of the latest relapse, but also the fact that the patient's disease over the years persistently manifested itself in lymph node drainage regions adjacent to or in the near proximity of the patient's breast implants, may be suggestive of a chronic antigenic stimulation eventually resulting in a malignant B-cell lymphoproliferation of DLBCL type. DLBCL histology has not previously been reported in possible association with breast implants. Disclosures: No relevant conflicts of interest to declare.

Interleukin-21-Induced Granzyme B-Expressing B Lymphocytes Infiltrate Tumors and Regulate T Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3278-3278
Author(s):  
Stefanie Lindner ◽  
Karen Dahlke ◽  
Kai Sontheimer ◽  
Magdalena Hagn ◽  
Christof Kaltenmeier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Granzyme B ◽  
Cell Receptor ◽  
Cell Expression

Abstract Abstract 3278 The role of B cells in tumor infiltrations is controversial. Different studies suggest that certain tumor-infiltrating B cell populations exhibit regulatory potential. Here, we demonstrate that the microenvironment of various solid tumors contains granzyme B (GrB)-expressing B cells adjacent to IL-21-providing T cells. GrB-mediated effector T cell modulation is already known from regulatory T cells (Treg) and plasmacytoid dendritic cells. We now show that IL-21 induces B cells to express high levels of GrB and to modulate T cell proliferation by GrB-dependent degradation of the T cell receptor z-chain. Detailed characterization of IL-21-induced GrB+ B cells reveals a CD19+CD38+CD1d+CD147+ phenotype and expression of additional regulatory molecules including IL-10, IDO and CD25. Of note, GrB induction is accompanied by both BCR- and TLR-mediated signals and GrB expression levels are influenced by B cell expression of CD5. In summary, we demonstrate that IL-21 induces GrB-expressing regulatory B cells, which are detected in tumor infiltrations, and which may contribute to the modulation of cellular adaptive immune responses by Treg-like mechanisms. Our findings may stimulate the development of novel diagnostic and cell therapeutic approaches to the management of malignant, autoimmune and graft-versus-host pathologies. Disclosures: No relevant conflicts of interest to declare.

Cardiovascular Risk in Rheumatoid Arthritis and Mechanistic Links: From Pathophysiology to Treatment

2020 ◽  
Vol 18 (5) ◽  
pp. 431-446 ◽  
Author(s):  
George E. Fragoulis ◽  
Ismini Panayotidis ◽  
Elena Nikiphorou
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Current Evidence ◽  
Pharmacological Intervention ◽  
Cvd Risk ◽  
The Past ◽  
Increased Risk ◽  
Cv Disease ◽  
Obesity Hypertension ◽  
Inflammatory Burden

Rheumatoid arthritis (RA) is an autoimmune inflammatory arthritis. Inflammation, however, can spread beyond the joints to involve other organs. During the past few years, it has been well recognized that RA associates with increased risk for cardiovascular (CV) disease (CVD) compared with the general population. This seems to be due not only to the increased occurrence in RA of classical CVD risk factors and comorbidities like smoking, obesity, hypertension, diabetes, metabolic syndrome, and others but also to the inflammatory burden that RA itself carries. This is not unexpected given the strong links between inflammation and atherosclerosis and CVD. It has been shown that inflammatory cytokines which are present in abundance in RA play a significant role in every step of plaque formation and rupture. Most of the therapeutic regimes used in RA treatment seem to offer significant benefits to that end. However, more studies are needed to clarify the effect of these drugs on various parameters, including the lipid profile. Of note, although pharmacological intervention significantly helps reduce the inflammatory burden and therefore the CVD risk, control of the so-called classical risk factors is equally important. Herein, we review the current evidence for the underlying pathogenic mechanisms linking inflammation with CVD in the context of RA and reflect on the possible impact of treatments used in RA.

Superantigens initiate cognate CD4+ T cell/ B cell interactions leading to early activation and proliferation of B cells

1995 ◽  
Vol 25 (9) ◽  
pp. 2539-2543 ◽  
Author(s):  
Reem Al-Daccak ◽  
Bassam Damaj ◽  
Paul H. Naccache ◽  
Walid Mourad
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Interactions ◽  
Cd4 T Cell ◽  
Early Activation

scholarly journals POS0387 ACPA STATUS CORRELATES WITH DIFFERENTIAL IMMUNE PROFILE OF RHEUMATOID ARTHRITIS PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 423.2-424
Author(s):  
A. Floudas ◽  
M. Canavan ◽  
T. McGarry ◽  
V. Krishna ◽  
S. Nagpal ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Synovial Tissue ◽  
Peripheral Blood ◽  
Flow Cytometric Analysis ◽  
Algorithm Analysis ◽  
Treat To Target ◽  
Tnf Α ◽  
Acpa Status

Background:Rheumatoid arthritis (RA) is a progressive erosive autoimmune disease that affects 1% of the world population. Anti-citrullinated protein autoantibodies (ACPA) are routinely used for the diagnosis of RA, however 20-30% of patients are ACPA negative. ACPA status is a delineator of RA disease endotypes with similar clinical manifestation but potentially different pathophysiology. Elucidating the underlying mechanisms of disease pathogenesis could inform a treat to target approach for both ACPA-positive and ACPA-negative RA patients.Objectives:To identify peripheral blood and synovial tissue immune population differences that associate with RA disease endotype.To identify unique RA patient synovial tissue gene signatures and enriched pathways that correlate with ACPA status.Methods:Detailed high dimensionality flow cytometric analysis with supervised and unsupervised algorithm analysis of ACPApos and ACPAneg RA patient peripheral blood and synovial tissue single cell suspensions. Ex vivo peripheral blood and synovial tissue T cell stimulation and cytokine production characterisation. RNAseq analysis with specific pathway enrichment analysis of APCApos and ACPAneg RA patient synovial tissue biopsies.Results:Detailed profiling based on high dimensionality flow cytometric analysis of key peripheral blood and synovial tissue immune populations including B cells, T follicular helper (Tfh) cells, T peripheral helper cells (Tph) and CD4 T cell proinflammatory cytokine responses with supervised and unsupervised algorithm analysis revealed unique RA patient peripheral blood B cell and Tfh cell profiles. ACPApos RA patients were characterised by significantly (*P=0.03) increased frequency of Tfh (CXCR5+CD4+) cells and distinct clustering influenced by increased switched (IgD-CD27+) and DN (IgD-CD27-) memory B cells compared to APCAneg RA patients. Surprisingly synovial tissue B cell subpopulation distribution was similar between ACPAneg and ACPApos RA patients, with significant accumulation of switched and double negative memory B cells, highlighting a key role for specific B cell subsets in both disease endotypes. Interestingly, synovial tissue CD4 T cell proinflammatory cytokine (TNF-α, IFN-γ, IL-2, GM-CSF, IL-17A, IL-22, IL-4) production was markedly different between ACPAneg and APCApos RA patients with hierarchical clustering and PCA analysis revealing endotype specific cytokine profiles with ACPAneg RA patient synovial T cells showing increased TNF-α (P=0.01) expression. RNAseq analysis of RA patient synovial tissue revealed significant disease endotype specific gene signatures with specific enrichment for B cell receptor signalling and T cell specific pathways in ACPApos compared to ACPAneg RA patients. Additionally, significantly different chemokine receptor expression based on RA patient ACPA status was observed with increased CXCR3 (P<0.001), CCR7 (P=0.002), and CCR2 (P=0.004) but decreased CXCR7 (P=0.007) expression in APCApos compared to ACPAneg RA patient synovial biopsies.Conclusion:ACPA status associates with unique synovial tissue immune cell and gene profile signatures highlighting differences in the underlying immunological mechanisms involved, therefore reinforcing the need for a treat to target approach for both endotypes of RA.Figure 1.RNAseq analysis of synovial tissue biopsies revealed specific T cell related pathway enrichment in ACPA positive compared to ACPA negative RA patients (n=50, analysis performed with the DESq2 and pathfindeR pipelines in R).Disclosure of Interests:Achilleas Floudas: None declared, Mary Canavan: None declared, Trudy McGarry Employee of: Novartis, Vinod Krishna Employee of: Janssen, Sunil Nagpal Employee of: Janssen, GSK, Douglas Veale Speakers bureau: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Consultant of: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Grant/research support from: Janssen, Abbvie, Pfizer, UCB, Ursula Fearon Speakers bureau: Abbvie, Grant/research support from: Janssen, Abbvie, Pfizer, UCB

scholarly journals CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation.

1996 ◽  
Vol 183 (4) ◽  
pp. 1707-1718 ◽  
Author(s):  
K F Byth ◽  
L A Conroy ◽  
S Howlett ◽  
A J Smith ◽  
J May ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cross Linking ◽  
Thymocyte Development ◽  
Double Positive

The CD45 transmembrane glycoprotein has been shown to be a protein phosphotyrosine phosphatase and to be important in signal transduction in T and B lymphocytes. We have employed gene targeting to create a strain of transgenic mice that completely lacks expression of all isoforms of CD45. The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls. The increase in B cell numbers is due to the specific expansion of two B cell subpopulations that express high levels of immunoglobulin (IgM) staining. T cell development is significantly inhibited in CD45-null animals at two distinct stages. The efficiency of the development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by twofold, subsequently the frequency of successful maturation of the double positive population into mature, single positive thymocytes is reduced by a further four- to fivefold. In addition, we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be induced normally in CD45-null thymocytes by non-TCR-mediated signals. Since both positive and negative selection require signals through the TCR complex, these findings suggest that CD45 is an important regulator of signal transduction via the TCR complex at multiple stages of T cell development. CD45 is absolutely required for the transmission of mitogenic signals via IgM and IgD. By contrast, CD45-null B cells proliferate as well as wild-type cells to CD40-mediated signals. The proliferation of B cells in response to CD38 cross-linking is significantly reduced but not abolished by the CD45-null mutation. We conclude that CD45 is not required at any stage during the generation of mature peripheral B cells, however its loss reveals a previously unrecognized role for CD45 in the regulation of certain subpopulations of B cells.

scholarly journals 702 Dual blockade of the PD-1 checkpoint pathway and the adenosinergic negative feedback signaling pathway with a PD-1/CD73 bispecific antibody for cancer immune therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A744-A744
Author(s):  
Tingting Zhong ◽  
Zhaoliang Huang ◽  
Xinghua Pang ◽  
Na Chen ◽  
Xiaoping Jin ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Negative Feedback ◽  
Immune Suppression ◽  
Specific Antibody ◽  
Cell Activation ◽  
Immune Therapy ◽  
B Cell Activation

BackgroundCD73 (ecto-5’-nucleotidase) is an ecto-nucleotidase that dephosphorylate AMP to form adenosine. Activation of adenosine signaling pathway in immune cells leads to the suppression of effector functions, down-regulate macrophage phagocytosis, inhibit pro-inflammatory cytokine release, as well as yield aberrantly differentiated dendritic cells producing pro-tumorigenic molecules.1 In the tumor microenvironment, adenosinergic negative feedback signaling facilitated immune suppression is considered an important mechanism for immune evasion of cancer cells.2 3 Combination of CD73 and anti-PD-1 antibody has shown promising activity in suppressing tumor growth. Hence, we developed AK119, an anti- human CD73 monoclonal antibody, and AK123,a bi-specific antibody targeting both PD-1 and CD73 for immune therapy of cancer.MethodsAK119 is a humanized antibody against CD73 and AK123 is a tetrameric bi-specific antibody targeting PD-1 and CD73. Binding assays of AK119 and AK123 to antigens, and antigen expressing cells were performed by using ELISA, Fortebio, and FACS assays. In-vitro assays to investigate the activity of AK119 and AK123 to inhibit CD73 enzymatic activity in modified CellTiter-Glo assay, to induce endocytosis of CD73, and to activate B cells were performed. Assay to evaluate AK123 activity on T cell activation were additionally performed. Moreover, the activities of AK119 and AK123 to mediate ADCC, CDC in CD73 expressing cells were also evaluated.ResultsAK119 and AK123 could bind to its respective soluble or membrane antigens expressing on PBMCs, MDA-MB-231, and U87-MG cells with high affinity. Results from cell-based assays indicated that AK119 and AK123 effectively inhibited nucleotidase enzyme activity of CD73, mediated endocytosis of CD73, and induced B cell activation by upregulating CD69 and CD83 expression on B cells, and showed more robust CD73 blocking and B cell activation activities compared to leading clinical candidate targeting CD73. AK123 could also block PD-1/PD-L1 interaction and enhance T cell activation.ConclusionsIn summary, AK119 and AK123 represent good preclinical biological properties, which support its further development as an anti-cancer immunotherapy or treating other diseases.ReferencesDeaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204:1257–65.Huang S, Apasov S, Koshiba M, Sitkovsky M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood. 1997; 90:1600–10.Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y, Tikhomirov OY, Blackburn MR, Biaggioni I,Carbone DP, Feoktistov I, et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 2008; 112:1822–31.

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