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Molecular Biomedicine Nov 2022Since the first monoclonal antibody drug, muromonab-CD3, was approved for marketing in 1986, 165 antibody drugs have been approved or are under regulatory review... (Review)
Review
Since the first monoclonal antibody drug, muromonab-CD3, was approved for marketing in 1986, 165 antibody drugs have been approved or are under regulatory review worldwide. With the approval of new drugs for treating a wide range of diseases, including cancer and autoimmune and metabolic disorders, the therapeutic antibody drug market has experienced explosive growth. Monoclonal antibodies have been sought after by many biopharmaceutical companies and scientific research institutes due to their high specificity, strong targeting abilities, low toxicity, side effects, and high development success rate. The related industries and markets are growing rapidly, and therapeutic antibodies are one of the most important research and development areas in the field of biology and medicine. In recent years, great progress has been made in the key technologies and theoretical innovations provided by therapeutic antibodies, including antibody-drug conjugates, antibody-conjugated nuclides, bispecific antibodies, nanobodies, and other antibody analogs. Additionally, therapeutic antibodies can be combined with technologies used in other fields to create new cross-fields, such as chimeric antigen receptor T cells (CAR-T), CAR-natural killer cells (CAR-NK), and other cell therapy. This review summarizes the latest approved or in regulatory review therapeutic antibodies that have been approved or that are under regulatory review worldwide, as well as clinical research on these approaches and their development, and outlines antibody discovery strategies that have emerged during the development of therapeutic antibodies, such as hybridoma technology, phage display, preparation of fully human antibody from transgenic mice, single B-cell antibody technology, and artificial intelligence-assisted antibody discovery.
PubMed: 36418786
DOI: 10.1186/s43556-022-00100-4 -
Lancet (London, England) Aug 2011Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab.
METHODS
In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697.
FINDINGS
763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group).
INTERPRETATION
Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children.
FUNDING
MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.
Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; C-Peptide; CD3 Complex; Canada; Child; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Eruptions; Europe; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; India; Insulin; Insulin-Secreting Cells; Israel; Male; Mexico; Muromonab-CD3; Treatment Outcome; United States; Young Adult
PubMed: 21719095
DOI: 10.1016/S0140-6736(11)60931-8 -
Journal of Immunotherapy (Hagerstown,... Sep 2009T cells can be engineered to express the genes of chimeric antigen receptors (CARs) that recognize tumor-associated antigens. We constructed and compared 2 CARs that...
T cells can be engineered to express the genes of chimeric antigen receptors (CARs) that recognize tumor-associated antigens. We constructed and compared 2 CARs that contained a single chain variable region moiety that recognized CD19. One CAR contained the signaling moiety of the 4-1BB molecule and the other did not. We selected the CAR that did not contain the 4-1BB moiety for further preclinical development. We demonstrated that gammaretroviruses encoding this receptor could transduce human T cells. Anti-CD19-CAR-transduced CD8+ and CD4+ T cells produced interferon-gamma and interleukin-2 specifically in response to CD19+ target cells. The transduced T cells specifically killed primary chronic lymphocytic leukemia (CLL) cells. We transduced T cells from CLL patients that had been previously treated with chemotherapy. We induced these T cells to proliferate sufficiently to provide enough cells for clinical adoptive T cell transfer with a protocol consisting of an initial stimulation with an anti-CD3 monoclonal antibody (OKT3) before transduction followed by a second OKT3 stimulation 7 days after transduction. This protocol was successfully adapted for use in CLL patients with high peripheral blood leukemia cell counts by depleting CD19+ cells before the initial OKT3 stimulation. In preparation for a clinical trial that will enroll patients with advanced B cell malignancies, we generated a producer cell clone that produces retroviruses encoding the anti-CD19 CAR, and we produced sufficient retroviral supernatant for the proposed clinical trial under good manufacturing practice conditions.
Topics: Antigens, CD19; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Gammaretrovirus; Genetic Vectors; Humans; Immunotherapy; Interferon-gamma; Interleukin-2; K562 Cells; Leukemia, Lymphocytic, Chronic, B-Cell; Muromonab-CD3; Receptors, Antigen; Receptors, Nerve Growth Factor; Recombinant Fusion Proteins; T-Lymphocytes; Transduction, Genetic
PubMed: 19561539
DOI: 10.1097/CJI.0b013e3181ac6138 -
MAbs 2023Bispecific antibodies continue to represent a growth area for antibody therapeutics, with roughly a third of molecules in clinical development being T-cell engagers that...
Bispecific antibodies continue to represent a growth area for antibody therapeutics, with roughly a third of molecules in clinical development being T-cell engagers that use an anti-CD3 binding arm. CD3 antibodies possessing cross-reactivity with cynomolgus monkey typically recognize a highly electronegative linear epitope at the extreme N-terminus of CD3 epsilon (CD3ε). Such antibodies have high isoelectric points and display problematic polyreactivity (correlated with poor pharmacokinetics for monospecific antibodies). Using insights from the crystal structure of anti-Hu/Cy CD3 antibody ADI-26906 in complex with CD3ε and antibody engineering using a yeast-based platform, we have derived high-affinity CD3 antibody variants with very low polyreactivity and significantly improved biophysical developability. Comparison of these variants with CD3 antibodies in the clinic (as part of bi- or multi-specifics) shows that affinity for CD3 is correlated with polyreactivity. Our engineered CD3 antibodies break this correlation, forming a broad affinity range with no to low polyreactivity. Such antibodies will enable bispecifics with improved pharmacokinetic and safety profiles and suggest engineering solutions that will benefit the large and growing sector of T-cell engagers.
Topics: Animals; Macaca fascicularis; Antibodies, Bispecific; T-Lymphocytes; CD3 Complex; Muromonab-CD3
PubMed: 36991534
DOI: 10.1080/19420862.2023.2189974 -
MAbs 2012Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As...
Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As more mAbs become available to physicians and patients, keeping track of the number, types, production cell lines, antigenic targets, and dates and locations of approvals has become challenging. Data are presented here for 34 mAbs that were approved in either Europe or the United States (US) as of March 2012, and nimotuzumab, which is marketed outside Europe and the US. Of the 34 mAbs, 28 (abciximab, rituximab, basiliximab, palivizumab, infliximab, trastuzumab, alemtuzumab, adalimumab, tositumomab-I131, cetuximab, ibrituximab tiuxetan, omalizumab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, certolizumab pegol, golimumab, canakinumab, catumaxomab, ustekinumab, tocilizumab, ofatumumab, denosumab, belimumab, ipilimumab, brentuximab) are currently marketed in Europe or the US. Data for six therapeutic mAbs (muromonab-CD3, nebacumab, edrecolomab, daclizumab, gemtuzumab ozogamicin, efalizumab) that were approved but have been withdrawn or discontinued from marketing in Europe or the US are also included.
Topics: Animals; Antibodies, Monoclonal; Drug Approval; Europe; Humans; Immunotherapy; Marketing; Product Recalls and Withdrawals; United States
PubMed: 22531442
DOI: 10.4161/mabs.19931 -
Experimental and Clinical... Aug 2016Kidney transplant remains the best type of renal replacement therapy in most patients with end-stage kidney disease, even in those with high immunologic risk.... (Review)
Review
Kidney transplant remains the best type of renal replacement therapy in most patients with end-stage kidney disease, even in those with high immunologic risk. Immunosuppression in these patients is regarded as more complex, owing to the higher risk of both acute and chronic rejection. The advent of induction immunosuppression has resulted in a lower incidence of acute rejection and consequently improved short-term patient and allograft outcomes. Indeed, the use of these agents, especially in high-risk recipients, has become standard of care at most transplant centers. Transplant physicians are constantly faced with the challenge of estimating the recipients' immunologic risk and tailoring their immunosuppression accordingly. This review article aims to provide an up-to-date evaluation of the various studies available, which investigated the use of induction agents in kidney transplant, specifically in high-risk recipients. It evaluates the use of the most frequently used polyclonal antibody (rabbit antithymocyte globulin) versus the less commonly used monoclonal antibody alemtuzumab, superseded agents such as muromonab-CD3, and potentially emerging agents such as rituximab, bortezomib, and eculizumab. With this systematic review, we hope to inform the scientific community and facilitate this controversial decision through the implementation of robust scientific evidence.
Topics: Drug Therapy, Combination; Evidence-Based Medicine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome
PubMed: 27041548
DOI: 10.6002/ect.2015.0328 -
Experimental and Clinical... Mar 2014Induction therapy after kidney transplantation is intensive immunosuppression in the initial days after transplant when the immune system of the recipient has the first... (Review)
Review
Induction therapy after kidney transplantation is intensive immunosuppression in the initial days after transplant when the immune system of the recipient has the first contact with donor antigens. Initial intensive immunosuppression may be required to prevent acute rejection and graft loss, and subsequent immunosuppression may be decreased to minimize adverse events associated with immunosuppressive drugs. Induction agents include lymphocyte-depleting antibodies such as rabbit antithymocyte globulin, alemtuzumab, muromonab-CD3, rituximab, and bortezomib; lymphocyte-nondepleting antibodies such as interleukin 2 receptor antibodies; and other discontinued or investigational agents such as efalizumab and alefacept. Induction therapy may be adjusted for special situations such as living-donor kidney transplant, pediatric transplant, hepatitis C virus-seropositive recipients, recipients who require desensitization, patients who are at risk for developing delayed graft function, and old donors. The optimal immunosuppressive regimen may vary, and clinical practice guidelines are available.
Topics: Acute Disease; Drug Administration Schedule; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Patient Selection; Risk Factors; Time Factors; Treatment Outcome
PubMed: 24635795
DOI: 10.6002/ect.25liver.l58 -
TouchREVIEWS in Endocrinology Nov 2023Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition characterized by the irreversible destruction of the β cells of the pancreas, which leads to a... (Review)
Review
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition characterized by the irreversible destruction of the β cells of the pancreas, which leads to a lifelong dependency on exogenous insulin. Despite the advancements in insulin delivery methods, the suboptimal outcomes of these methods have triggered the search for therapies that may prevent or reverse the disease. Given the autoimmune aetiology of T1DM, therapies counteracting the immune-mediated destruction of the β-cells are the obvious target. Although several treatment strategies have been attempted to target cellular, humoral and innate immunity, very few have had a clinically meaningful impact. Of all the available immunomodulatory agents, cluster of differentiation (CD) 3 antibodies have exhibited the most promising preclinical and clinical results. Muromonab-CD3, which also happened to be a murine CD3 antibody, was the first monoclonal antibody approved for clinical use and was primarily indicated for graft rejection. The adverse effects associated with muromonab-CD3 led to its withdrawal. Teplizumab, a newer CD3 antibody, has a better side-effect profile because of its humanized nature and non-Fc-receptor-binding domain. In November 2022, teplizumab became the first immunomodulatory agent to be licensed by the US Food and Drug Administration for delaying the onset of T1DM in high-risk adults and children over 8 years old. The mechanism seems to be enhancing regulatory T-cell activity and promoting immune tolerance. This article reviews the mechanism of action and the clinical trials of teplizumab in individuals with T1DM or at risk of developing the disease.
PubMed: 38187075
DOI: 10.17925/EE.2023.19.2.7 -
Antibodies (Basel, Switzerland) Nov 2022Since the first approval of the anti-CD3 recombinant monoclonal antibody (mAb), muromonab-CD3, a mouse antibody for the prevention of transplant rejection, by the US... (Review)
Review
Since the first approval of the anti-CD3 recombinant monoclonal antibody (mAb), muromonab-CD3, a mouse antibody for the prevention of transplant rejection, by the US Food and Drug Administration (FDA) in 1986, mAb therapeutics have become increasingly important to medical care. A wealth of information about mAbs regarding their structure, stability, post-translation modifications, and the relationship between modification and function has been reported. Yet, substantial resources are still required throughout development and commercialization to have appropriate control strategies to maintain consistent product quality, safety, and efficacy. A typical feature of mAbs is charge heterogeneity, which stems from a variety of modifications, including modifications that are common to many mAbs or unique to a specific molecule or process. Charge heterogeneity is highly sensitive to process changes and thus a good indicator of a robust process. It is a high-risk quality attribute that could potentially fail the specification and comparability required for batch disposition. Failure to meet product specifications or comparability can substantially affect clinical development timelines. To mitigate these risks, the general rule is to maintain a comparable charge profile when process changes are inevitably introduced during development and even after commercialization. Otherwise, new peaks or varied levels of acidic and basic species must be justified based on scientific knowledge and clinical experience for a specific molecule. Here, we summarize the current understanding of mAb charge variants and outline risk-based control strategies to support process development and ultimately commercialization.
PubMed: 36412839
DOI: 10.3390/antib11040073