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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Daratumumab (Darzalex™) is a first-in-class humanized IgG1 antibody targeting the CD38 epitope. It is used for the treatment of multiple myeloma and non-Hodgkin’s lymphomas. CD38 is expressed on multiple immune system cell types, and is highly expressed in hematological malignancies, including multiple myeloma. Daratumumab was approved in the USA in 2015 for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. The US FDA granted breakthrough therapy designation to daratumumab in 2013, and approval in 2015 was made via the agency’s accelerated approval program. In 2018, the FDA expanded the approval of daratumumab for use in combination with bortezomib, melphalan, and prednisone to include the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
Immunology of T Cells in AIDS: Dynamics Revealed by Eight-Color Flow Cytometry
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Mario Roederer, Stephen C. De Rosa, Leonore A. Herzenberg, Leonard A. Herzenberg
Indeed, Giorgi and colleagues have elegantly demonstrated the power of antigen density measurements for predicting progression to AIDS. They quantitated the expression of an activation marker, CD38, on CD8 T cells and found that higher expression was correlated with faster progression to clinical AIDS [4]. In fact, the CD38 density measurement was considerably more powerful than either CD4 counts or viral load measurements. Even in combination with these two standard measurements, CD38 antigen density is a powerful predictor for rate of progression to AIDS. We have recently extended Giorgi and associates’ findings by examining a cohort of patients that is relatively advanced in disease (CD4 < 200/pi). We found that CD38 is a powerful predictor for progression to death in relatively advanced-stage patients (Figure 2).
The Immune System During HIV-1 Infection
Published in Niel T. Constantine, Johnny D. Callahan, Douglas M. Watts, Retroviral Testing, 2020
Niel T. Constantine, Johnny D. Callahan, Douglas M. Watts
Normally, T lymphocytes (CD4+ and CD8+) account for 70 to 90% of all lymphocytes. Their numbers are generally near 1600 cells per cubic millimeter (μl), with CD4+ cells accounting for about 1000 and CD8+ about 500. The decrease in CD4+ T cells noted during HIV infection is usually gradual (50 to 100 cells per cubic millimeter/year), with levels being about 600 within the first year after infection (Figure 13). CD4+ T levels are highly prognostic for predicting survival, especially during late disease. Approximately 80% of individuals will die within 1 year when the CD4+ T cells fall to 10%. High levels of CD38+CD8+ cells are characteristic of late HIV disease and are highly prognostic for HIV disease progression.
Isatuximab in multiple myeloma
Published in Expert Opinion on Biological Therapy, 2023
Enrica Antonia Martino, Antonella Bruzzese, Enrico Iaccino, Francesco Mendicino, Selena Mimmi, Eugenio Lucia, Virginia Olivito, Antonino Neri, Fortunato Morabito, Ernesto Vigna, Massimo Gentile
CD38 is a type II transmembrane protein expressed in immune cells and modulates leukocyte migration, activation process, and calcium signaling. In normal conditions, CD38 is expressed at low levels in immune cells [1], while healthy individuals and MM patients show significantly higher CD38 expression in plasma cells [2]. Isa determines MM cell death through complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) through the binding of Fcγ receptors on immune effector cells with consequent release of toxic agents, such as perforin and granzyme. Isa can also directly induce MM cell death through caspase-dependent apoptosis, modulate the enzymatic activity of CD38, and enhance the natural killer cell- and T-cell-mediated immune response [2]. Although Dara acts similarly to Isa, the mechanism of action of the two mAbs is slightly different. First, the two drugs target different CD38 epitopes. Furthermore, daratumumab must be combined with cross-linking agents to induce apoptosis, while Isa can directly induce cell death [1,2] (Figure 1).
TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity
Published in mAbs, 2022
Harshad S. Ugamraj, Kevin Dang, Laure-Hélène Ouisse, Benjamin Buelow, Eduardo N. Chini, Giulia Castello, James Allison, Starlynn C Clarke, Laura M. Davison, Roland Buelow, Rong Deng, Suhasini Iyer, Ute Schellenberger, Sankar N. Manika, Shipra Bijpuria, Astrid Musnier, Anne Poupon, Maria Cristina Cuturi, Wim van Schooten, Pranjali Dalvi
CD38 is a 45 kDa type II transmembrane protein expressed on immune cells, including macrophages, T cells, B cells, and natural killer (NK) cells, and is prominently upregulated on activated immune cells, thus serving as a biomarker for active infections, inflammatory diseases, autoimmune conditions, and inflammation associated with aging, or “inflammaging”.7,8 CD38 is an ecto-enzyme that hydrolyzes nicotinamide adenine dinucleotide (NAD+) to form adenine diphosphate ribose (ADPR) and nicotinamide (NAM); secondarily, it degrades NAD+ via cyclase activity yielding cyclic adenine dinucleotide (cADPR). Other substrates of CD38 include nicotinamide adenine dinucleotide phosphate (NADP+) and nicotinamide mononucleotide (NMN), a critical precursor of NAD+ in the salvage pathway, preventing its uptake into cells and its conversion to NAD+ intracellularly.4 NAD+ plays a crucial role in several metabolic processes that maintain energy balance, DNA repair, and signaling.9 Decreases in NAD+ are associated with natural aging, and NAD+ boosting is associated with increased life- and health-spans in animals.10 Therefore, TNB-738-mediated inhibition of CD38 represents a promising approach to treat a plethora of acute and chronic conditions associated with NAD+ decline.
Novel BCMA-OR-CD38 tandem-dual chimeric antigen receptor T cells robustly control multiple myeloma
Published in OncoImmunology, 2021
Yaru Feng, Xiuying Liu, Xiaorui Li, Yating Zhou, Zhiru Song, Jing Zhang, Bingjie Shi, Jianxun Wang
Human CD38 antigen (45 kDa) is a single-chain type II transmembrane glycoprotein, and > 90% of malignant plasma cells from patients with MM show surface expression of CD38.32 In addition, CD38 is also expressed by cells of the immune system, including T-cells, B-cells, NK-cells, macrophages, and dendritic cells,33 but the expression levels are lower compared to MM cells.34 Thus, CD38 has been regarded as a feasible target for the treatment of MM, and several studies have indicated the efficacy and safety of CD38 monoclonal antibodies in clinical applications.35,36 Remarkably, an anti-CD38 antibody (Daratumumab) has been approved for the treatment of RRMM by the FDA.37 Encouraged by these results, many researchers have explored the feasibility of developing CAR-T cell therapy targeting CD38 molecules. Early preclinical studies had shown that CD38 CAR-T cells were capable of proliferating, producing cytokines and effectively eliminating CD38+ myeloma cells.22 Recently, several clinical trials on anti-CD38 CAR-T-cell treatments of MM are in progress (NCT03464916, NCT03754764). Our study found that CD38-specific CAR-T cells showed significant lytic activity against myeloma cells in vivo and in vitro, and these cells showed no defects in ex vivo expansion.