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

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 onceweekly 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 &lt; .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.</p

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

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 onceweekly 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 &lt; .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.</p

Identification and characterization of the zebra finch (Taeniopygia guttata) sperm proteome

Spermatozoa exhibit remarkable variability in size, shape, and performance. Our understanding of the molecular basis of this variation, however, is limited, especially in avian taxa. The zebra finch (Taeniopygia guttata) is a model organism in the study of avian sperm biology and sperm competition. Using LC-MS based proteomics, we identify and describe 494 proteins of the zebra finch sperm proteome (ZfSP). Gene ontology and associated bioinformatics analyses revealed a rich repertoire of proteins essential to sperm structure and function, including proteins linked to metabolism and energetics, as well as tubulin binding and microtubule related functions. The ZfSP also contained a number of immunity and defense proteins and proteins linked to sperm motility and sperm-egg interactions. Additionally, while most proteins in the ZfSP appear to be evolutionarily constrained, a small subset of proteins are evolving rapidly. Finally, in a comparison with the sperm proteome of the domestic chicken, we found an enrichment of proteins linked to catalytic activity and cytoskeleton related processes. As the first described passerine sperm proteome, and one of only two characterized avian sperm proteomes, the ZfSP provides a significant step towards a platform for studies of the molecular basis of sperm function and evolution in birds

Sperm Proteome Maturation in the Mouse Epididymis

<div><p>In mammals, transit through the epididymis, which involves the acquisition, loss and modification of proteins, is required to confer motility and fertilization competency to sperm. The overall dynamics of maturation is poorly understood, and a systems level understanding of the complex maturation process will provide valuable new information about changes occurring during epididymal transport. We report the proteomes of sperm collected from the caput, corpus and cauda segments of the mouse epididymis, identifying 1536, 1720 and 1234 proteins respectively. This study identified 765 proteins that are present in sperm obtained from all three segments. We identified 1766 proteins that are potentially added (732) or removed (1034) from sperm during epididymal transit. Phenotypic analyses of the caput, corpus and cauda sperm proteomes identified 60 proteins that have known sperm phenotypes when mutated, or absent from sperm. Our analysis indicates that as much as one-third of proteins with known sperm phenotypes are added to sperm during epididymal transit. GO analyses revealed that cauda sperm are enriched for specific functions including sperm-egg recognition and motility, consistent with the observation that sperm acquire motility and fertilization competency during transit through the epididymis. In addition, GO analyses revealed that the immunity protein profile of sperm changes during sperm maturation. Finally, we identified components of the 26S proteasome, the immunoproteasome, and a proteasome activator in mature sperm.</p></div

Region-specific enrichment of proteins unique to each segment and organized by GO categories related to cell location.

<p>Enriched categories are color-coded: caput (red), corpus (green) and corpus (blue) indicating the general overall differences in these protein datasets. The darker the node, the greater enrichment in the indicated categories. White, or gray-colored nodes indicate no specific enrichment between each of the three protein lists.</p

Mouse caput, corpus and cauda sperm proteins with known associated sperm phenotypes.

<p>^aProteins found to be added to sperm during epididymal transit in this study are indicated in <b>bold</b>.</p><p>Mouse caput, corpus and cauda sperm proteins with known associated sperm phenotypes.</p

GO term enrichment in proteins added during epididymal transit^a.

<p>^aCytoscape was used to identified enriched protein groups compared to proteins identified as "removed" (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140650#pone.0140650.g002" target="_blank">Fig 2</a>).</p><p>GO term enrichment in proteins added during epididymal transit<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140650#t005fn001" target="_blank">^a</a>.</p

Summary of sperm proteomes derived from the three major regions of the mouse epididymis.

<p>(A) Graphical representation of epididymis. Different colors represent the 6 distinct transcriptional segments previously identified [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140650#pone.0140650.ref014" target="_blank">14</a>]. Numbers within the epididymis indicate the number of proteins identified in the caputSP (1536), corpusSP (1720) and caudaSP (1234), respectively. Proteins added (protein gain), or removed (protein loss), from sperm between segments are displayed above and below the epididymis. In total, 732 proteins were added and 1034 proteins were removed (1766 total) from sperm during epididymal transit. (B) Venn diagram illustrating the overlap of protein identification between the three epididymal segments. 765 proteins were found to be common to sperm from all segments. (C) Proportion of proteins gained and lost by segment.</p

Enriched biological process GO categories for proteins added and removed from sperm during epididymal transit.

<p>Network biological process diagram indicating functional enrichment of GO categories for proteins added (green) and removed (red) from sperm during epididymal transit. Color legend at top indicates range of overlap shared by the datasets. The varying shades of color represent nodes and clusters of functional GO categories biased towards proteins added (green) or removed (removed) during transit through the epididymis.</p

Summary of Mass Spectrometry Results.

<p>Summary of Mass Spectrometry Results.</p