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Transplant International : Official... Jul 2013Induction therapy, the initial high-dose bolus of immunosuppression given perioperatively to transplant patients, is almost ubiquitous in pancreas transplantation.... (Review)
Review
Induction therapy, the initial high-dose bolus of immunosuppression given perioperatively to transplant patients, is almost ubiquitous in pancreas transplantation. Despite the frequent use, scientific data on the risks and benefits of induction therapy are scarce, especially as it concerns use specifically for pancreas transplantation. Indeed, none of the currently used induction agents are approved as induction therapy for pancreas transplantation, yet potential benefit is largely extrapolated from trials in kidney transplant recipients. This review summarizes which induction therapy agents are available both now and historically, their mechanisms of action, and provides an overview of the published literature describing the use of these agents in simultaneous pancreas-kidney transplant and solitary pancreas transplant recipients. In summary, there are two multicenter randomized trials, several single-center randomized trials, and many other single-center descriptive reports. Overall, the main benefit of induction therapy is the ability to wean steroids earlier, and the main downside is a higher risk of opportunistic infections. Despite a lack of solid evidence, over 90% of pancreas transplants performed annually in the United States receive some type of induction immunosuppression.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Humans; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Pancreas Transplantation; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins
PubMed: 23672537
DOI: 10.1111/tri.12122 -
MAbs 2021Recent years have seen unparalleled development of microfluidic applications for antibody discovery in both academic and pharmaceutical research. Microfluidics can...
Recent years have seen unparalleled development of microfluidic applications for antibody discovery in both academic and pharmaceutical research. Microfluidics can support native chain-paired library generation as well as direct screening of antibody secreting cells obtained by rodent immunization or from the human peripheral blood. While broad diversities of neutralizing antibodies against infectious diseases such as HIV, Ebola, or COVID-19 have been identified from convalescent individuals, microfluidics can expedite therapeutic antibody discovery for cancer or immunological disease indications. In this study, a commercially available microfluidic device, Cyto-Mine, was used for the rapid identification of natively paired antibodies from rodents or human donors screened for specific binding to recombinant antigens, for direct screening with cells expressing the target of interest, and, to our knowledge for the first time, for direct broad functional IgG antibody screening in droplets. The process time from cell preparation to confirmed recombinant antibodies was four weeks. Application of this or similar microfluidic devices and methodologies can accelerate and enhance pharmaceutical antibody hit discovery.
Topics: Animals; Antibodies, Bacterial; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; Antibody Specificity; Antigens; Antigens, Neoplasm; Blood Preservation; COVID-19; Fluorescence Resonance Energy Transfer; Humans; Hybridomas; Immunoglobulin G; Immunomagnetic Separation; Lab-On-A-Chip Devices; Mice; Microfluidics; Muromonab-CD3; Plasma Cells; Recombinant Proteins; SARS-CoV-2; Tetanus Toxoid; Vaccination
PubMed: 34586015
DOI: 10.1080/19420862.2021.1978130 -
MAbs 2010The use of antibodies in transplantation dates to 1986 when muromonab CD3, a monoclonal antibody (mAb) targeting CD3, was first approved for prevention and treatment of... (Review)
Review
The use of antibodies in transplantation dates to 1986 when muromonab CD3, a monoclonal antibody (mAb) targeting CD3, was first approved for prevention and treatment of renal allograft rejection. These agents have largely been used in a brief adjunctive manner to provide immunosuppression during the initial period after solid organ transplantation or during an episode of acute rejection. Recent advances in our understanding of transplant immunology have allowed emergence of numerous new mAbs, targeting co-stimulatory signals, cell surface receptors and novel protein constructs. During the next decade, transplant professionals will increasingly require knowledge of the mechanisms and pharmacologic characteristics of these novel therapeutic agents.
Topics: Animals; Antibodies, Monoclonal; Clinical Trials as Topic; Graft Rejection; Humans; Immunosuppressive Agents; Organ Transplantation
PubMed: 20948291
DOI: 10.4161/mabs.2.6.13586 -
New Biotechnology Sep 2023Antibody-based cancer therapies have been evolving at a rapid pace in the pharmaceutical market. Bispecific antibody-drug conjugates that engage immune cells to target...
Antibody-based cancer therapies have been evolving at a rapid pace in the pharmaceutical market. Bispecific antibody-drug conjugates that engage immune cells to target and kill cancer cells with precision have inspired the development of immunotherapy. Miniaturized antibody fragments such as diabodies, nanobodies, or single-chain variable fragments (scFvs) hold great promise as antibody-drug conjugates as they specifically target tumor tissue and can penetrate it. Here, we optimized the soluble periplasmic expression of the scFv OKT3 comprising the variable V and V domains of the mouse anti-human CD3 antibody muromonab-CD3 (trade name Orthoclone OKT3) in E. coli. By an expansion of the genetic code, we site-specifically incorporated the reactive non-canonical amino acid N-((2-azidoethoxy)carbonyl)-L-lysine (AzK) into scFv OKT3 using an orthogonal pyrrolysyl-tRNA synthetase/tRNA pair. To confirm the AzK incorporation and to demonstrate the accessibility of the reactive azide group, we conjugated a fluorophore to scFv OKT3 AzK variants by copper-free strain-promoted alkyne-azide cycloaddition ('click chemistry'). The scFv OKT3 wild type and the AzK variants bound T cells at nanomolar concentrations. In this study, a 'ready-to-click' scFv OKT3 was successfully developed for future applications, e.g. as controlled anti-T cell antibody-drug conjugate or bispecific T cell engager and for imaging immune T cell migration in cancers.
Topics: Animals; Mice; Muromonab-CD3; Escherichia coli; Azides; Receptors, Antigen, T-Cell; Neoplasms; Genetic Code; Immunoconjugates
PubMed: 37257818
DOI: 10.1016/j.nbt.2023.05.007 -
Blood Oct 1992The proliferation and in vitro cytolytic activity of interleukin-2 (IL-2)-activated and anti-CD3 + IL-2-stimulated marrow mononuclear cells (MMC) and peripheral blood... (Comparative Study)
Comparative Study
The proliferation and in vitro cytolytic activity of interleukin-2 (IL-2)-activated and anti-CD3 + IL-2-stimulated marrow mononuclear cells (MMC) and peripheral blood mononuclear cells (PBMC) were studied. Samples from 8 normal donors, 15 patients with acute lymphoblastic leukemia (ALL), and 7 patients with non-Hodgkin's lymphoma (NHL) in remission were cultured in IL-2 (100 U/mL) or IL-2 (100 U/mL) plus anti-CD3 (10 ng/mL). MMC as well as PBMC samples demonstrated significant synergy between IL-2 and anti-CD3 in the promotion of proliferation as measured by 3H thymidine incorporation on day 5 (P less than .001) or fold increase in cell number on day 14. Cryopreserved marrow specimens had equally rapid proliferation as fresh MMC when cultured in the presence of anti-CD3 + IL-2. Anti-CD3 concentrations of 3, 11, 33, and 100 ng/mL augmented proliferation similarly in the presence of IL-2 (0.1 to 100 U/mL). Mean fold increases in cell number of both marrow- and blood-derived cultures after 14 days were significantly higher for anti-CD3 + IL-2-stimulated cultures compared with cultures stimulated with IL-2 only (50- to 200-fold increase in cell number; P = .01). Comparison of remission MMC and PBMC from ALL and NHL patients with normal controls showed equivalent growth rates of activated cultures at 7, 14, and 21 days. Marrow purging with immunotoxin anti-CD19 pokeweed antiviral protein plus 4HC had no significant effect on proliferation of anti-CD3 + IL-2-stimulated MMC cultures in patients with ALL. Cytolytic activity of IL-2- and IL-2 + anti-CD3-activated PBMC and MMC cultures was assessed in 51Cr release assays using K562 (natural killer ([NK]-sensitive), Daudi (Burkitt's lymphoma-, NK-resistant), and Nalm-6 (ALL-, lymphokine-activated killer [LAK]-resistant) cell lines and cryopreserved ALL blasts. Cytolytic activity on a per-cell basis (percent cytotoxicity at an effector:target ratio of 30:1) was similar in IL-2-activated PBMC- and MMC-derived cultures from ALL patients. MMC activated with anti-CD3 plus IL-2 killed Daudi significantly less well than IL-2-activated cultures on days 12 and 19 (P = .03); no significant differences were observed in lysis of LAK-resistant Nalm-6 or cryopreserved ALL blast targets. Dose response of anti-CD3 augmentation of Daudi and Nalm-6 killing was different in IL-2- and IL-2 + anti-CD3-stimulated cultures.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Bone Marrow; Bone Marrow Cells; CD3 Complex; Cell Division; Cell Survival; Cells, Cultured; Cryopreservation; Interleukin-2; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Kinetics; Lymphoma, Non-Hodgkin; Monocytes; Muromonab-CD3; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors
PubMed: 1391948
DOI: No ID Found -
Medecine Sciences : M/S Dec 2009Polyclonal anti-lymphoyctes antibodies were first successfully used in the 1970 in organ transplantation, but ten years later, monoclonal antibodies (mAb) emerged as a... (Review)
Review
Polyclonal anti-lymphoyctes antibodies were first successfully used in the 1970 in organ transplantation, but ten years later, monoclonal antibodies (mAb) emerged as a new class of immunosuppressive agents in transplantation with the potential to target highly specifically immune cells responsible for acute rejection. Some have proved their efficacy, such as mAb recognizing CD3- and CD25-positive T cells and have been extensively studied in clinical trials. Others such as mAb against CD52 and CD20, are still under investigation; finally, the next challenge is, based on our improved understanding of the mechanisms of immune recognition and allograft rejection, to use these mAb either alone or in combination with standard immunosuppressive regimens to manipulate the allogenic response to reach antigen-specific tolerance desired in solid-organ transplantation.
Topics: Animals; Antibodies, Monoclonal; Antigens, CD; Antigens, CD20; Antigens, Neoplasm; Antilymphocyte Serum; CD52 Antigen; Clinical Trials as Topic; Drug Evaluation, Preclinical; Glycoproteins; Graft Rejection; Humans; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Muromonab-CD3; T-Lymphocytes, Regulatory; Transplantation Immunology
PubMed: 20035690
DOI: 10.1051/medsci/200925121121 -
Journal of Fungi (Basel, Switzerland) Mar 2021Since 1985 when the first agent targeting antigens on the surface of lymphocytes was approved (muromonab-CD3), a multitude of such therapies have been used in children... (Review)
Review
Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies.
Since 1985 when the first agent targeting antigens on the surface of lymphocytes was approved (muromonab-CD3), a multitude of such therapies have been used in children with hematologic malignancies. A detailed literature review until January 2021 was conducted regarding pediatric patient populations treated with agents that target CD2 (alefacept), CD3 (bispecific T-cell engager [BiTE] blinatumomab), CD19 (denintuzumab mafodotin, B43, BiTEs blinatumomab and DT2219ARL, the immunotoxin combotox, and chimeric antigen receptor [CAR] T-cell therapies tisagenlecleucel and axicabtagene ciloleucel), CD20 (rituximab and biosimilars, Y-ibritumomab tiuxetan, ofatumumab, and obinutuzumab), CD22 (epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, BiTE DT2219ARL, and the immunotoxin combotox), CD25 (basiliximab and inolimomab), CD30 (brentuximab vedotin and iratumumab), CD33 (gemtuzumab ozogamicin), CD38 (daratumumab and isatuximab), CD52 (alemtuzumab), CD66b (Y-labelled BW 250/183), CD248 (ontuxizumab) and immune checkpoint inhibitors against CTLA-4 (CD152; abatacept, ipilimumab and tremelimumab) or with PD-1/PD-L1 blockade (CD279/CD274; atezolizumab, avelumab, camrelizumab, durvalumab, nivolumab and pembrolizumab). The aim of this narrative review is to describe treatment-related invasive fungal diseases (IFDs) of each category of agents. IFDs are very common in patients under blinatumomab, inotuzumab ozogamicin, basiliximab, gemtuzumab ozogamicin, alemtuzumab, and tisagenlecleucel and uncommon in patients treated with moxetumomab pasudotox, brentuximab vedotin, abatacept, ipilimumab, pembrolizumab and avelumab. Although this new era of precision medicine shows promising outcomes of targeted therapies in children with leukemia or lymphoma, the results of this review stress the necessity for ongoing surveillance and suggest the need for antifungal prophylaxis in cases where IFDs are very common complications.
PubMed: 33807678
DOI: 10.3390/jof7030186 -
Clinical and Experimental Immunology Sep 2003
Review
Topics: Autoimmune Diseases; CD3 Complex; Graft Rejection; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Muromonab-CD3; Organ Transplantation; Receptors, Fc; Transplantation, Homologous
PubMed: 12930354
DOI: 10.1046/j.1365-2249.2003.02227.x -
Cytometry. Part B, Clinical Cytometry Jan 2022
Topics: Flow Cytometry; Humans; Immunophenotyping; Kidney Transplantation; Lymphoma, T-Cell, Peripheral; Muromonab-CD3
PubMed: 33955673
DOI: 10.1002/cyto.b.22004 -
British Journal of Clinical Pharmacology Aug 2013To determine if cytokine release with a solid phase assay is predictive of adverse responses for a range of therapeutic mAbs.
AIM
To determine if cytokine release with a solid phase assay is predictive of adverse responses for a range of therapeutic mAbs.
METHODS
Cytokine ELISAs and a multi-array system were used to compare responses generated by different therapeutic mAbs using a solid phase assay. Flow cytometry was employed to determine the cellular source of those cytokines.
RESULTS
Only TGN1412 and muromonab-CD3 stimulated CD4+ T-cell mediated cytokine release characterized by significant (all P < 0.0001) IFNγ, TNFα, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17 and IL-22 release, comparable with T-cell mitogen. Significantly greater (P < 0.0001) IL-2 release with TGN1412 (2894-6051 pg ml⁻¹) compared with muromonab-CD3 (62-262 pg ml⁻¹) differentiated otherwise comparable cytokine responses. Likewise, TGN1412 stimulated significantly more (P = 0.0001) IL-2 producing CD4+ T-cells than muromonab-CD3 and induced Th1, Th2, Th17 and Th22 subsets that co-release this cytokine. Significant TNFα release was observed with bevacizumab (P = 0.0001), trastuzumab (P = 0.0031) and alemtuzumab (P = 0.0177), but no significant IL-2 release. TGN1412 and muromonab-CD3 caused pro-inflammatory cytokine release despite significantly (both P < 0.0001) increasing numbers of T-cells with a regulatory phenotype.
CONCLUSIONS
The severity of the adverse response to TGN1412 compared with muromonab-CD3 and other therapeutic mAbs correlates with the level of IL-2 release.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Cytokines; Drug-Related Side Effects and Adverse Reactions; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Interleukin-2; Muromonab-CD3; Research Design; Risk Assessment
PubMed: 23701319
DOI: 10.1111/bcp.12165