Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation.

ABSTRACT: Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.

Hydrogen sulfide donor NaHS reduces organ injury in a rat model of pneumococcal pneumosepsis, associated with improved bio-energetic status.

Sepsis is characterized by a generalized inflammatory response and organ failure, associated with mitochondrial dysfunction. Hydrogen sulfide donor NaHS has anti-inflammatory properties, is able to reduce metabolism and can preserve mitochondrial morphology and function. Rats were challenged with live Streptococcus pneumonia or saline and infused with NaHS (36 µmol/kg/h) or vehicle. Lung and kidney injury markers were measured as well as mitochondrial function, viability and biogenesis. Infusion of NaHS reduced heart rate and body temperature, indicative of a hypo-metabolic state. NaHS infusion reduced sepsis-related lung and kidney injury, while host defense remained intact, as reflected by unchanged bacterial outgrowth. The reduction in organ injury was associated with a reversal of a fall in active oxidative phosphorylation with a concomitant decrease in ATP levels and ATP/ADP ratio. Preservation of mitochondrial respiration was associated with increased mitochondrial expression of α-tubulin and protein kinase C-ε, which acts as regulators of respiration. Mitochondrial damage was decreased by NaHS, as suggested by a reduction in mitochondrial DNA leakage in the lung. Also, NaHS treatment was associated with upregulation of peroxisome proliferator-activated receptor-γ coactivator 1α, with a subsequent increase in transcription of mitochondrial respiratory subunits. These findings indicate that NaHS reduces organ injury in pneumosepsis, possibly via preservation of oxidative phosphorylation and thereby ATP synthesis as well as by promoting mitochondrial biogenesis. Further studies on the involvement of mitochondria in sepsis are required.