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Daratumumab is a CD38 monoclonal antibody recently approved for the treatment of multiple myeloma (MM). We report daratumumab pharmacokinetic data from GEN501, a phase I/II dose-escalation (0.005–24 mg/kg) and dose-expansion (8 or 16 mg/kg) study, and SIRIUS, a phase II study (8 or 16 mg/kg), in relapsed or refractory MM. Noncompartmental analysis was conducted to characterize daratumumab pharmacokinetics, and, in both studies, daratumumab exhibited nonlinear pharmacokinetic characteristics. Decreasing daratumumab clearance with increasing dose suggests saturation of target-mediated clearance at higher dose levels, whereas decreasing clearance over time with repeated dosing may be due to tumor burden reductions as CD38-positive cells are eliminated. These and other pharmacokinetic data analyses support the use of the recommended dose regimen of daratumumab (16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter) to rapidly saturate target-mediated clearance during weekly dosing and maintain saturation when dosing every 2 or 4 weeks.

In a study involving patients with refractory multiple myeloma, the anti-CD38 antibody daratumumab in combination with bortezomib and dexamethasone resulted in longer progression-free survival and a higher rate of response than bortezomib and dexamethasone alone. Multiple myeloma is associated with organ dysfunction, including bone lesions, anemia, renal insufficiency, and hypercalcemia. 1 , 2 Proteasome inhibitors (e.g., bortezomib) in combination with glucocorticoids are standard regimens for relapsed or relapsed and refractory multiple myeloma 3 (definitions of these terms are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org) and have contributed considerably to patient survival. 4 Nevertheless, almost all patients will have a relapse. Daratumumab is a human IgGκ monoclonal antibody that targets CD38, which is highly expressed on myeloma cells and other hematopoietic cell types. 5 , 6 Daratumumab has direct and indirect antitumor activity and diverse . . .

AbstractObjectiveTo assess the efficacy and safety of CM313, an anti-CD38 monoclonal antibody, in adults with persistent or chronic primary immune thrombocytopenia.DesignMulticentre, randomised, placebo controlled, phase 2 trial.SettingFive hospitals in China, 16 January to 11 June 2024.Participants45 patients aged ≥18 years with persistent or chronic immune thrombocytopenia who failed to respond to, or relapsed after, glucocorticoid treatment but had previously responded to standard first line treatment.InterventionsPatients were randomised to receive intravenous CM313 (16 mg/kg) or placebo weekly for eight weeks.Main outcome measuresThe primary outcome was overall response rate (at least two consecutive platelet counts ≥30×109/L, a minimum doubling from baseline, and no bleeding) at week 8. A secondary outcome was time to the first two consecutive platelet counts ≥50×109/L.ResultsOf 56 patients screened, 45 were randomised to receive CM313 (n=30) or placebo (n=15). At week 8, the overall response rate was higher in the CM313 group (83%; 25/30) compared with placebo group (20%; 3/15): difference 63.3% (95% confidence interval 33.7% to 81.3%; P<0.001). The median time to a platelet count of ≥50×109/L was one week in the CM313 group but was not reached in the placebo group (P<0.001). The median cumulative response duration for platelet counts ≥50×109/L was 18 weeks in the CM313 group versus three weeks in the placebo group (P=0.004). Treatment emergent adverse events occurred in 87% (26/30) of patients in the CM313 group and 80% (12/15) in the placebo group, with infusion related reactions and petechiae being the most common.ConclusionCM313 showed a favourable safety profile and encouraging efficacy in adults with persistent or chronic primary immune thrombocytopenia, characterised by rapid increase in platelet count, sustained platelet responses, and manageable adverse events.Trial registrationClinicalTrials.gov NCT06199089.

CM313, a novel humanized anti‐CD38 monoclonal antibody, has demonstrated therapeutic potential in autoimmune diseases. This Phase 1 trial evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy participants following single ascending doses of CM313. Fifty‐one participants received CM313 or placebo by SC injection at doses of 150 mg (1:1), 300 mg (2:1), and 600 mg (2:1), or by IV infusion at 8 mg/kg (2:1). All completed the trial. Treatment‐emergent adverse events occurred in 90.9% of CM313‐treated participants and 83.3% of placebo‐treated participants, all mild or moderate. No serious adverse events were reported. SC injections of CM313 demonstrated a notably lower incidence of infusion‐related reactions (600 mg SC: 20%) than IV infusion (8 mg/kg IV: 60%). CM313 exhibited nonlinear pharmacokinetics. Following a single SC dose, the median Tmax was 2.00–3.00 days, mean Cmax was 4.75–87.40 μg/mL, mean AUC0‐t was 20.29–1262.50 day*μg/mL, mean Vz/F was 2.63–21.20 L, mean clearance was 0.50–7.90 L/day, and mean half‐life was 1.85–3.90 days. The bioavailability of the 600 mg SC dose was 66% of the 8 mg/kg IV dose. CM313 induced rapid and sustained reductions in total IgA, IgE, IgG, and IgM levels by 40%–80% from baseline. Both SC and IV formulations demonstrated potent CD38 binding activity and markedly depleted NK cells by ≥ 90% within 2 days. CM313 also achieved 80%–90% CD38 receptor occupancy on B cells, T cells, and monocytes within 1 week. Overall, single doses of CM313 demonstrated favorable safety, tolerability, PK, and PD in healthy participants. Trial Registration: ClinicalTrials.gov (NCT06285227)

CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca 2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38 -/- ) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38 -/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38 -/- mice. Depolarization-induced OT secretion and Ca 2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38 -/- mice; this was mimicked by CD38 metabolite antagonists in CD38 +/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders. A niceness protein? An unexpected activity of the transmembrane signalling glycoprotein CD38 suggests that it has a novel role in the regulation of maternal and social behaviours. Found on the surface of many immune cells, CD38 is involved in the fertilization of invertebrate eggs, in HIV infection, cancers and diabetes. The high levels of CD38 in the brain, previously rather puzzling, make more sense now it has been found that it regulates plasma levels of the hormone oxytocin in mice. Mice lacking CD38 show defective nurturing behaviour (in females) and social behaviour (in males). This makes CD38 a possible factor in neurodevelopment disorders.

Background. Some human immunodeficiency virus (HlV)-infected individuals are not able to achieve a normal CD4⁺ T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size. Methods. Thirty treated subjects with CD4⁺ T cell counts of < 350 cells/mm³ despite viral suppression for ≥1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <. 3 copy/mL) and a change in the percentage of CD38⁺ HLA-DR⁺ CD8⁺ T cells in peripheral blood mononuclear cells (PBMCs). Results. The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue. Conclusions. Low-level viremia is not likely to be a significant cause of suboptimal CD4⁺ T cell gains during HIV treatment. Clinical Trials Registration. NCT00631449.

Aims/Background Recent agents have profoundly reshaped the multiple myeloma (MM) landscape. Their real‐world impacts need to be assessed over the long term. Methods EMMY is a non‐interventional, prospective dynamic cohort, conducted in France, since 2017, with 900 patients enrolled each year. Newly diagnosed MM (NDMM) who initiated a treatment from 2017 to 2020 are here described. Results A total of 1036 non‐transplant eligible (NTE) patients (median age: 74.9 years) and 561 patients who received autologous stem cell transplantation (ASCT) (median age: 60.6 years) were enrolled. For ASCT patients, a shift in induction treatment from bortezomib‐thalidomide‐dexamethasone (VTd) (29.1%) to bortezomib‐lenalidomide‐dexamethasone (VRd) (55.1%) marked the period. Maintenance treatment with R after ASCT became a standard (75% of patients). In NTE patients, R‐based regimens were increasingly used from 29.4% in 2017 (of whom Rd.: 17.0%, VRd: 10.6%) to 73.3% in 2020 (of whom Rd.: 21.8%, VRd: 48.5%). Median progression‐free survival (mPFS) was 46.5 months (95% CI: 37.8–50.6) and 18.7 months (95% CI: 16.3–20.8) in ASCT and NTE patients, respectively. In the ASCT group, patients treated with and without R maintenance had a mPFS of 51.8 (95% CI: 44.1–NA) and 29.6 months (95% CI: 21.8–40.9), respectively. In the NTE group, the mPFS was 26.3 (95% CI: 21.9–30.9) and 14.6 months (95% CI: 11.9–17.7) in patients who received an R‐based and non‐R‐based regimen, respectively. The estimated 48‐month overall survival rates were 89% (95% CI: 84.5–92.2) and 63% (95% CI: 58.5–67.1) for ASCT and NTE patients, respectively. Conclusions The 2017–2020 period was marked by the expansion of R use in both NDMM ASCT and NTE patients. A total of 1036 non‐transplant eligible (NTE) patients and 561 patients who received autologous stem cell transplantation (ASCT) were enrolled in Emmy. In the ASCT group, patients treated with and without R maintenance had a mPFS of 51.8 (95% CI: 44.1–NA) and 29.6 months (95% CI: 21.8–40.9), respectively. In the NTE group, the mPFS was 26.3 (95% CI: 21.9–30.9) and 14.6 months (95% CI: 11.9–17.7) in patients who received an R‐based and non‐R‐based regimen, respectively. The 2017–2020 period was marked by the expansion of R use in both NMDD ASCT and NTE patients.

The oxytocin (OT) system, critically involved in social bonding, may also impinge on spirituality, which is the belief in a meaningful life imbued with a sense of connection to a Higher Power and/or the world. Midlife male participants ( N  = 83) were randomly assigned to receive intranasal OT or placebo. In exploratory analyses, participants were also genotyped for polymorphisms in two genes critical for OT signaling, the oxytocin receptor gene ( OXTR rs53576) and CD38 (rs6449182 and rs3796863). Results showed that intranasal OT increased self-reported spirituality on two separate measures and this effect remained significant a week later. It also boosted participants’ experience of specific positive emotions during meditation, at both explicit and implicit levels. Furthermore, the effect of OT on spirituality was moderated by OT-related genotypes. These results provide the first experimental evidence that spirituality, endorsed by millions worldwide, appears to be supported by OT.

Effectiveness of seasonal influenza vaccination varies between individuals and might be affected by vaccination history among other factors. Here we show, by monitoring frequencies of CD4 T cells specific to the conserved hemagglutinin epitope HA 118-132 and titres of IgG against the corresponding recombinant hemagglutinin protein, that antigen-specific CD4 T cell and antibody responses are closely linked to pre-existing immunity and vaccine history. Upon immunization, a strong early reaction is observed in all vaccine naïve participants and also in vaccine experienced individuals who have not received the respective seasonal vaccine in the previous year. This response is characterized by HA 118-132 specific CD4 T cells with a follicular helper T cell phenotype and by ascending titers of hemagglutinin-specific antibodies from baseline to day 28 following vaccination. This trend was observed in only a proportion of those participants who received the seasonal vaccine the year preceding the study. Regardless of history, levels of pre-existing antibodies and CD127 expression on CD4 T cells at baseline were the strongest predictors of robust early response. Thus, both pre-existing immunity and vaccine history contribute to the response to seasonal influenza vaccines. Understanding individual variations in the response to seasonal influenza vaccines has broad implications from basic immunology to public health. Here authors show that influenza hemagglutinin-specific T and B cell responses are determined by the pre-vaccination immune phenotype and vaccination history of recipients.

Daratumumab was associated with impressive antitumor responses, including complete and very good partial responses, in heavily pretreated patients with myeloma. Infusion reactions were the main adverse effect. Current therapies, including proteasome inhibitors and immunomodulatory agents, have improved outcomes substantially in patients with multiple myeloma. 1 Unfortunately, the majority of these patients have a relapse and have limited treatment options after exposure to these classes of agents. 2 , 3 Patients with disease that is refractory to both proteasome inhibitors and immunomodulatory drugs have poor prognoses; the estimated median overall survival is 9 months, and the estimated event-free survival is 5 months at best. 2 , 3 CD38 is a 45-kD, type II transmembrane glycoprotein that associates with cell-surface receptors in lipid rafts, regulates cytoplasmic Ca 2+ flux, and mediates signal transduction in lymphoid . . .