Depletion Of Plasma Cells Research Articles

Immunomodulation of severe graves' disease: graves'-plasma cell depletion (PCD) trial

Immunomodulation of severe graves' disease: graves'-plasma cell depletion (PCD) trial

Daratumumab for De-sensitization of Donor Specific Antibodies: Is it a Quicker and Easier way?

Antibodies directed against donor-specific HLA loci (DSA) has been proved as a main culprit for graft rejection, more specifically in HLA mismatched and haplo-identical transplant settings. There is no standardized regimen to manage the presence of DSAs in allogeneic stem cell transplantations (allo-SCTs). Most widely regimen includes combination of rituximab (anti CD20 antibody), Immunoglobulin (IVIG), plasma exchange, and buffy coat infusion, which is costly and time-consuming. Daratumumab (anti CD38 monoclonal antibody) is an effective therapeutic agent to deplete plasma cells and hence, it has a potential to reduce DSA. It has been utilized widely in solid organ transplantation for this purpose. We used this agent in two haplo-identical transplant patients to eliminate or reduce DSA. We observed definite either reduction or elimination in DSA levels in these cases and we could perform haplo-identical transplantation without much delay and with successful primary engraftment in both scenarios. We emphasize that literature on real-world utilization of daratumumab in allo-SCTs is limited. However, it has been utilized widely in solid organ transplantation for this purpose. Our experience with daratumumab regarding effective reduction of DSA followed by successful engraftment might encourage its use in de-sensitization protocols without much delay in transplantation.

P2RX4 Inhibition: Finally, a Silver Bullet for Long-lived Plasma Cells Depletion?

P2RX4 Inhibition: Finally, a Silver Bullet for Long-lived Plasma Cells Depletion?

Acute rejection post lung transplant.

To review what is currently known about the pathogenesis, diagnosis, treatment, and prevention of acute rejection (AR) in lung transplantation. Epigenomic and transcriptomic methods are gaining traction as tools for earlier detection of AR, which still remains primarily a histopathologic diagnosis. Acute rejection is a common cause of early posttransplant lung graft dysfunction and increases the risk of chronic rejection. Detection and diagnosis of AR is primarily based on histopathology, but noninvasive molecular methods are undergoing investigation. Two subtypes of AR exist: acute cellular rejection (ACR) and antibody-mediated rejection (AMR). Both can have varied clinical presentation, ranging from asymptomatic to fulminant ARDS, and can present simultaneously. Diagnosis of ACR requires transbronchial biopsy; AMR requires the additional measuring of circulating donor-specific antibody (DSA) levels. First-line treatment in ACR is increased immunosuppression (pulse-dose or tapered dose glucocorticoids); refractory cases may need antibody-based lymphodepletion therapy. First line treatment in AMR focuses on circulating DSA removal with B and plasma cell depletion; plasmapheresis, intravenous human immunoglobulin (IVIG), bortezomib, and rituximab are often employed.

Effectiveness of combined plasma cell therapy and costimulation blockade based desensitization regimen in heart transplant candidates.

Desensitization is one of the strategies to reduce antibodies and facilitate heart transplantation in highly sensitized patients. We describe our center's desensitization experience with combination of plasma cell (PC) depletion therapy (with proteasome inhibitor or daratumumab) and costimulation blockade (with belatacept). We reviewed five highly sensitized patients who underwent desensitization therapy with plasma cell depletion and costimulation blockade. We evaluated the response to therapy by measuring the changes in cPRA, average MFI, and number of positive beads>5000MFI. Five patients, mean age of 56 (37-66) years with average cPRA of 98% at 5000 MFI underwent desensitization therapy. After desensitization, mean cPRA decreased from 98% to 70% (p=.09), average number of beads>5000 MFI decreased from 59 to 37 (p=.15), and average MFI of beads>5000 MFI decreased from 16713 to 13074 (p=.26). Combined PC depletion and CoB could be a reasonable strategy for sustained reduction in antibodies in highly sensitized patients being listed for heart transplantation.

CM313, a Novel Anti-CD38 Antibody, As a Potential Treatment for Primary Immune Thrombocytopenia: A Phase II Trial

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Antiplatelet-specific plasma cells (PCs) have been identified in ITP patients, making PCs depletion a potential treatment for ITP. CM313, a novel anti-CD38 monoclonal antibody currently under investigation in a phase I trial for multiple myeloma, has demonstrated targeted depletion of CD38-positive cells, including PCs. This phase II trial (NCT05694767) was designed to assess the safety and efficacy of CM313 in ITP patients. Methods: The open-label phase II trial consisted of a 4-week screening period, an 8-week treatment period, and a 16-week follow-up period. The main inclusion criteria were patients (age ≥18 years) with ITP and a platelet count <30×10 9/L, who did not response to or relapsed after glucocorticoid therapy and at least one second-line therapy (including rituximab and/or thrombopoietin receptor agonists [TPO-RAs]). Eligible patients received CM313 intravenously at a dose of 16 mg/kg weekly for a total of 8 weeks. The participants were requested to maintain the stable doses of glucocorticoids or TPO-RAs for 4 weeks prior to receiving the first dose without dose escalation during the study. Prophylactic medication, including glucocorticoids, antihistamines, and acetaminophen, was administered to all patients before and after the infusion. The primary endpoints were the percentage of patients with a platelet count ≥50×10 9/L within 8 weeks after the first dose (platelet count must be consecutive on at least 2 occasions with an interval of at least 1 day) and the incidence/severity of adverse events during the study period. Results： As of June 30, 2023, a total of 21 patients had been enrolled in the study and 7 subjects had completed 8 doses of the treatment with at least 8 weeks of follow-up. The 7 subjects consisted of 2 males and 5 females, with a median age of 40 years (range 18-56), a median weight of 62 kg (range 52-93), a median duration of ITP of 30 months (range 12-200) and a median baseline platelet count of 8×10 9/L (range 2-24). Of the 7 patients, 100.0% (7/7) achieved a platelet count ≥50×10 9/L within 8 weeks after the first dose, with a median time to response of 1 week (range 1-3). Furthermore, 4 out of 7 patients (57.1%) maintained a platelet count of ≥50×10 9/L until week 16, while 2 patients experienced a relapse at week 6 and 1 patient had a relapse at week 13. Platelet count (expressed as the median with the interquartile range) of the 7 patients from baseline to week 23 are shown in Figure 1. Of all 21 patients, 6 (6/21, 28.6%) had an infusion-related reaction (IRR) at the first dose but none at subsequent doses. The severity of IRR was grade 1 or 2 (according to CTCAE version 5.0). Conclusion: CM313, a novel anti-CD38 monoclonal antibody, has demonstrated tolerable safety and preliminary efficacy in refractory/relapsed ITP patients. Figure 1: Platelet count in 7 patients.

Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed?

Antibody-mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46%vs. 7%) than in allotransplantation (3%vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti-donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti-inflammatory therapy. Depletion or neutralization of anti-pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG-degrading enzymes do not deplete IgM. Despite the expression of human complement-regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti-C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell-targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti-inflammatory agents, anti-IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti-inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ-source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD-L1, HLA E, and/or HLA-G.

#6402 IMPACT OF DARATUMUMAB AND BELATACEPT ON HLA ANTIBODIES IN KIDNEY TRANSPLANT CANDIDATES WITH 100% CPRA: EARLY RESULTS OF ATTAIN (ITN090ST)

Abstract Background and Aims Despite high allocation priority, <10% of kidney transplant candidates with cPRA 100% can find a compatible donor. Current desensitization strategies are ineffective due to antibody rebound. Adding costimulation blockade to plasma cell (PC) depletion prevents antibody rebound in nonhuman primates by countering nodal B cell and Tfh expansion. Method ATTAIN is a pilot, phase I/II trial of daratumumab, a CD38 mAb used in multiple myeloma, plus belatacept, a high affinity CTLA4-Ig, to desensitize kidney transplant candidates with cPRA ≥99.9%. Enrolled subjects receive daratumumab (6 doses: 8 mg/kg) and belatacept (4 doses: 10 mg/kg) over 10 weeks with bone marrow and blood assessments pre-and post-treatment. The primary efficacy endpoint (PE) is a composite of (1) elimination of ≥1 HLA antibody specificity, (2) ≥50% reduction in the MFI of ≥3 HLA antibody specificities, or (3) kidney transplant from a previously incompatible donor. Target accrual is 15, enrolled in 2 cohorts (5+10). Results Cohort 1 (n = 5, mean age 44, 60% with previous transplant) has been enrolled and treated, with 5-31 weeks follow-up to date. The treatment was tolerated well in all 5 patients who showed a significant reduction in most HLA antibodies after treatment without manifestation of rebound. 3 of 5 participants reached the PE and 5 of 5 had >50% bone marrow (BM) PC depletion. One patient received a kidney transplant from a previously incompatible deceased donor and is doing well at 7 months post-transplant without rejection or rebound of HLA antibody. Treatment was temporarily paused in 3 subjects due to AEs (acute cholecystitis and COVID, upper GI bleed, fevers); no cases of opportunistic infection or malignancy occurred. Conclusion A novel HLA desensitization regimen consisting of PC depletion with Daratumumab and costimulatory blockade with Belatacept appears safe and successful in the ongoing ATTAIN clinical trial. In the initial subject, this regimen led to transplant without HLA antibody rebound or acute rejection. Longer follow-up and additional subjects are needed to confirm these promising results. ATTAIN (NCT04827979) is a trial conducted by the Immune Tolerance Network and sponsored by NIAID (award UM1AI109565).

Targeting plasma cells in systemic autoimmune rheumatic diseases – Promises and pitfalls

Plasma cells are the antibody secretors of the immune system. Continuous antibody secretion over years can provide long-term immune protection but could also be held responsible for long-lasting autoimmunity in case of self-reactive plasma cells. Systemic autoimmune rheumatic diseases (ARD) affect multiple organ systems and are associated with a plethora of different autoantibodies. Two prototypic systemic ARDs are systemic lupus erythematosus (SLE) and Sjögren's disease (SjD). Both diseases are characterized by B-cell hyperactivity and the production of autoantibodies against nuclear antigens. Analogues to other immune cells, different subsets of plasma cells have been described. Plasma cell subsets are often defined dependent on their current state of maturation, that also depend on the precursor B-cell subset from which they derived. But, a universal definition of plasma cell subsets is not available so far. Furthermore, the ability for long-term survival and effector functions may differ, potentially in a disease-specific manner. Characterization of plasma cell subsets and their specificity in individual patients can help to choose a suitable targeting approach for either a broad or more selective plasma cell depletion. Targeting plasma cells in systemic ARDs is currently challenging because of side effects or varying depletion efficacies in the tissue. Recent developments, however, like antigen-specific targeting and CAR-T-cell therapy might open up major benefits for patients beyond current treatment options.

Abstract CT013: Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma

Abstract Background: MM remains incurable and new tx options are needed, especially in heavily pre-treated R/R pts. REGN5459, a BCMAxCD3 bispecific Ab, binds to BCMA on MM cells and with low affinity to CD3 on T cells, triggering T-cell activation and plasma cell depletion with low cytokine release preclinically. This first-in-human study aimed to assess the safety, tolerability, and preliminary anti-tumor activity of REGN5459 monotherapy in pts with R/R MM. Methods: Eligible pts had received ≥3 prior lines of tx including an anti-CD38 Ab, proteasome inhibitor, and immunomodulatory drug, and had exhausted all available tx options. Pts could receive REGN5459 until progression/intolerable toxicity. Primary objectives were to assess safety, tolerability, dose limiting toxicities (DLTs), and determine the recommended Ph 2 dose (RP2D) of REGN5459 (Ph 1) and assess efficacy of REGN5459 (Ph 2) per ORR. Results: As of June 9, 2022, 43 pts were enrolled (Ph 1, 33; Ph 2, 10): median age 67 yrs (range, 26-85), 51% female, 16% high cytogenetic risk, 14% extramedullary plasmacytoma, 37% R-ISS Stage III disease, 61% triple-class refractory, and median of 5 (range, 2-9) prior lines of tx. In Ph 1, one DLT was reported in a pt receiving the highest dose (900 mg; Gr 3 hypoxia, pt later found to have primary lung cancer). RP2D was identified as 480 mg. All pts enrolled had ≥1 TEAE, 74% had Gr ≥3 TEAEs. TEAEs all-Gr in ≥30% of pts were CRS (54%), fatigue (44%), neutropenia (37%), anemia (35%), cough (30%), and diarrhea (30%). Gr ≥3 TEAEs in ≥15% of pts were neutropenia (37%), anemia (26%), lymphopenia (23%), thrombocytopenia (19%), and hypertension (16%). CRS Gr 1, 2, and 3 were reported in 47%, 2%, and 5%, respectively; there was no Gr 4 or 5 CRS. No Gr 3 CRS with RP2D. Tocilizumab was used in 19% and steroids in 9% of pts. One pt developed ICANS (2%, Gr 2). Incidence of serious TEAEs and TEAEs leading to tx discontinuation was 63% and 16%. Infections occurred in 61% (37% Gr ≥3). After data-cutoff, two deaths due to COVID pneumonia and COVID infection have been reported. ORR was 67% (58% ≥VGPR) for the entire cohort and 100% (85% ≥VGPR; 15% sCR; 39% CR) among pts receiving the RP2D (n=13). Median follow-up was 7 mos (range, 1-26) with longest response ongoing for 22+ mos. Median time to response was 0.8 mos. Median DOR was NR (95% CI, 12-NE); 12-mo DOR for RP2D was 66.7% (95% CI, 5.4-94.5). Of pts in ≥CR with available MRD results (n=8), 50% were MRD negative at the 10−5 threshold. Conclusion: These initial data show that REGN5459 has acceptable safety/tolerability in R/R MM with most CRS of low grade and low incidence of ICANS. Modulation of CD3 affinity on bispecific Abs to maximize tumor killing, and mitigate CRS and T-cell exhaustion, warrants further research. Efficacy in this heavily pre-treated cohort was encouraging, with 100% ORR with the RP2D. Updated data will be presented at the meeting. Citation Format: Attaya Suvannasankha, Prashant Kapoor, Matthew J. Pianko, Joshua Richter, Anita D'Souza, Larry D. Anderson, Andrew Magyar, Oluwaseun Aina, Anita Boyapati, Damien Cronier, Nikhil Singh, Karen Rodriguez-Lorenc, Glenn S. Kroog, Hans C. Lee. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT013.

A mechanism for the elimination of IgE plasma cells

Abstract The proper regulation of IgE production safeguards against allergic disease, highlighting the importance of mechanisms that restrict IgE plasma cell (PC) survival. IgE PCs have unusually high surface B cell receptor (BCR) expression, yet the functional consequences of ligating this receptor are unknown. Here, we found that BCR ligation induced BCR signaling in IgE PCs followed by their elimination. In cell culture, exposure of IgE PCs to cognate antigen or anti-BCR antibodies induced apoptosis. IgE PC depletion correlated with the affinity, avidity, amount, and duration of antigen exposure and required the BCR signalosome components Syk, BLNK, and PLCγ2. In mice with a PC-specific impairment of BCR signaling, the abundance of IgE PCs was selectively increased. Conversely, BCR ligation by injection of cognate antigen or anti-IgE depleted IgE PCs. These findings establish a mechanism for the elimination of IgE PCs through BCR ligation. This has important implications for allergen tolerance and immunotherapy as well as anti-IgE monoclonal antibody treatments. This research was supported by the National Institute of Allergy and Infections Diseases of the National Institutes of Health under Award Number R01AI130470; the Program for Breakthrough Biomedical Research, which is partially funded by the Sandler Foundation; the Sandler Asthma Basic Research Center; and the Cardiovascular Research Institute at the University of California, San Francisco. C.D.C.A. was a Pew Scholar in the Biomedical Sciences, supported by The Pew Charitable Trusts. A.K.W-V was supported by a Doctoral Foreign Study Award from the Canadian Institute of Health Research, funding reference number DFD-170769. D.M.T. and M.J.R. were funded by National Health and Medical Research Council (NHMRC) Australia by an Investigator Award (APP1175411) and Ideas Grant (APP1185294), respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline.

Despite the uncertainty of the pathogenesis of systemic lupus erythematosus, novel small molecules targeting specific intracellular mechanisms of immune cells are being developed to reverse the pathophysiological processes. These targeted molecules have the advantages of convenient administration, lower production costs, and the lack of immunogenicity. The Janus kinases, Bruton's tyrosine kinases, and spleen tyrosine kinases are important enzymes for activating downstream signals from various receptors on immune cells that include cytokines, growth factor, hormones, Fc, CD40, and B-cell receptors. Suppression of these kinases impairs cellular activation, differentiation, and survival, leading to diminished cytokine actions and autoantibody secretion. Intracellular protein degradation by immunoproteasomes, levered by the cereblon E3 ubiquitin ligase complex, is an essential process for the regulation of cellular functions and survival. Modulation of the immunoproteasomes and cereblon leads to depletion of long-lived plasma cells, reduced plasmablast differentiation, and production of autoantibodies and interferon-α. The sphingosine 1-phosphate/sphingosine 1-phosphate receptor-1 pathway is responsible for lymphocyte trafficking, regulatory T-cell/Th17 cell homeostasis, and vascular permeability. Sphingosine 1-phosphate receptor-1 modulators limit the trafficking of autoreactive lymphocytes across the blood-brain barrier, increase regulatory T-cell function, and decrease production of autoantibodies and type I interferons. This article summarizes the development of these targeted small molecules in the treatment of systemic lupus erythematosus, and the future prospect for precision medicine.

Effects of invivo CXCR4 blockade and proteasome inhibition on bone marrow plasma cells in HLA-sensitized kidney transplant candidates

To date, plasma cell (PC)–targeted therapies have been limited by suboptimal PC depletion and antibody rebound. We hypothesized this is partly because of PC residence in protective bone marrow (BM) microenvironments. The purpose of this proof-of-concept study was to examine the effects of the CXCR4 antagonist, plerixafor, on PC BM residence; its safety profile (alone and in combination with a proteasome inhibitor, bortezomib); and the transcriptional effect on BMPCs in HLA-sensitized kidney transplant candidates. Participants were enrolled into 3 groups: group A (n = 4), plerixafor monotherapy; and groups B (n = 4) and C (n = 4), plerixafor and bortezomib combinations. CD34+ stem cell and PC levels increased in the blood after plerixafor treatment. PC recovery from BM aspirates varied depending on the dose of plerixafor and bortezomib. Single-cell RNA sequencing on BMPCs from 3 group C participants pretreatment and posttreatment revealed multiple populations of PCs, with a posttreatment enrichment of oxidative phosphorylation, proteasome assembly, cytoplasmic translation, and autophagy-related genes. Murine studies demonstrated dually inhibiting the proteasome and autophagy resulted in greater BMPC death than did monotherapies. In conclusion, this pilot study revealed anticipated effects of combined plerixafor and bortezomib on BMPCs, an acceptable safety profile, and suggests the potential for autophagy inhibitors in desensitization regimens.

B cell receptor ligation induces IgE plasma cell elimination.

The proper regulation of IgE production safeguards against allergic disease, highlighting the importance of mechanisms that restrict IgE plasma cell (PC) survival. IgE PCs have unusually high surface B cell receptor (BCR) expression, yet the functional consequences of ligating this receptor are unknown. Here, we found that BCR ligation induced BCR signaling in IgE PCs followed by their elimination. In cell culture, exposure of IgE PCs to cognate antigen or anti-BCR antibodies induced apoptosis. IgE PC depletion correlated with the affinity, avidity, amount, and duration of antigen exposure and required the BCR signalosome components Syk, BLNK, and PLCγ2. In mice with a PC-specific impairment of BCR signaling, the abundance of IgE PCs was selectively increased. Conversely, BCR ligation by injection of cognate antigen or anti-IgE depleted IgE PCs. These findings establish a mechanism for the elimination of IgE PCs through BCR ligation. This has important implications for allergen tolerance and immunotherapy as well as anti-IgE monoclonal antibody treatments.

Commentary: Case report: Daratumumab treatment in pre-transplant alloimmunization and severe hemolytic anemia.

Pereda et al. recently reported three cases in which daratumumab was utilized to reduce the 36 burden of red blood cell (RBC) and human leukocyte antigen (HLA) alloantibodies (1). These 37 cases support the need for further investigation into the potential use of daratumumab and related 38 plasma cell depletion therapies for patients with significant alloimmunization. However, the 39 authors' cases, particularly cases 1 and 2 in which the authors describe patients with sickle cell 40 disease (SCD) and multiple RBC antibodies, lack sufficient immunohematology and transfusion 41 details to reliably conclude the effectiveness and safety of daratumumab to reduce and existing alloantibodies can persist despite daratumumab treatment (3-6). Secondly, the 80 authors fail to acknowledge the possibility that the alloantibodies may have disappeared naturally 81 through the phenomenon of evanescence. Numerous studies have shown that many patients' 82 RBC alloantibodies will decline in titer to levels below a detectable threshold without further 83 exposure (7-9). Though the loss of all antibodies due to evanescence may be less likely, not 84 accounting for this potential mechanism of a waning antibody is concerning. 85 86 Furthermore, literature demonstrates that even if these antibodies have become undetectable, 87 these patients may still be at risk for DHTRs (10-13).

Rituximab and Bortezomib for Patients with Newly Diagnosed Acquired Haemophilia: Single Arm, Single Center, Prospective Phase 2 Study

Introduction Acquired haemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against factor VIII (FVIII). The most common IST treatment used are Steroids-based regimens. However, patients with AHA are often elderly with comorbidities. Steroids-based regimens have significant side effects in patients with AHA. In particular, the risk of dying from infection appears to be higher than the risk of fatal bleeds today. This dilemma highlights the lack of safe and rapid response IST therapy in AHA. Bortezomib targets plasma cells rather than B cells and has reported efficacy in refractory AHA. It is an attractive agent because it depletes plasma cells that can continue to produce autoantibody even after CD20-positive B cells have been depleted by rituximab. The combination of bortezomib and rituximab regimen showed rapid response without severe adverse event in refractory and relapsed warm autoimmune hemolytic anemia. This phase 2, prospective, single-center study was designed to evaluate the efficacy and safety of rituximab and bortezomib (RB) treatment regimen in newly diagnosed AHA patients. Methods All patients 18 years of age or older who met the following criteria were considered as eligible candidates for this study: 1) plasma FVIII activity (FVIII:C) <50 l/dl, detectable inhibitor to FVIII. 2) newly diagnosed without any IST treatment. After obtaining the written informed consent from the patients, the information of demographic and medical history were collected and laboratory tests were performed.The patients were received the following regimens: Rituximab 375mg/m2 intravenous infusion on day 0 and bortezomib 1.3 mg/m2 subcutaneous on day 1,4,8,11. Best supportive care, including administration of hemostatic treatment and blood product transfusions if needed were used. Safety was evaluated according to NCI-CTCAE v4.0. Results From March 2018 to May 2022, 30 patients were eligible for the study. The baseline characteristics of the patients are summarized in Table 1. Overall, 19 patients were male (63.3%). The median age was 53.5 years (range 22 - 90 years). The underlying disorders that could be associated with AHA included rheumatoid arthritis, systemic lupus erythematosus and pemphigus. One patient was diagnosed at her postpartum. One patient was diagnosed soon after surgery. Traditional Chinese medicine was suspected as the inducement in one patient. No patient in our cohort was reported to have coexisting malignancy. 24 patients (80.0%) were regarded as idiopathic AHA. The median time from disease onset to the diagnosis was 36.5 days (range 10-249 days). The median FVIII activity at baseline was 1.5 IU/ml (range 0 to 10.4 IU/ml), and the median inhibitor concentration was 25.6 BU/ ml (range 2.7 to 600 BU/ ml). The bleeding event that precipitated diagnosis was reported as spontaneous in 27 patients (90.0%), by surgery in 3 patients (10.0%). All patients presented with bleeding diathesis as listed in Table 1. Sixteen patients (61.5%) received haemostatic treatment for initial bleeding, all of them received prothrombin complex concentrate (PCC). Nine patients experienced further bleeding after the treatment of BR. All patients completed protocol treatment. Overall, 23 patients (76.7%) achieved CR, 6 patients (20.0%) achieved PR and 1 patients died of cardiac events 3 month after last dose of bortezomib. The ORR was 96.7%. Median time to CR was 74 days (range 12-179 days). After a median follow-up of 39 months (range 3-50 months), one patient had relapse of the disease, 2 months after achieved CR. Major toxicities and adverse events are summarized in Table 2. One patient (3.8%) had grade 3 neutropenia; One patient (3.8%) had grade 4 thrombocytopenia and grade 3 thrombocytopenia each. Eight patients experienced infectious fever, including 2 grade 3 and 2 (7.7%) grade 4. Five patients (19.2%) developed grade 1-2 peripheral neuropathy.No treatment-related deaths occurred. Conclusion Here we report the results of a phase 2 prospective study of newly diagnosed AHA. This study confirmed that rituximab plus bortezomib was an efficient and safe regimen with ORR of 96.7%, and the median time to CR was 74 days.This trial was registered at www.clinicaltrials.gov as #NCT03700229. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Emerging strategies for antibody-mediated rejection.

Antibody-mediated rejection (AMR) is the leading cause of kidney graft loss. Very few treatment options are available to the clinician to counter this disease process. In this review we describe the available therapeutics and the novel approaches that are being currently developed. AMR treatment requires a multidrug approach. Imlifidase, a new immunoglobulin G cleaving agent, may prove to be the perfect replacement of apheresis. New complement blockers other than eculizumab are in development in order to block acute kidney damage in the delicate phase following antibody removal. Plasma cell depletion is being explored in chronic AMR: studies are in progress with daratumumab and felzartamab. Interleukin 6 inhibition is generating enthusiasm in the chronic setting with preliminary encouraging results. In acute AMR, the clinicians will have to remove the antibodies, avoid rebound and block specific damage effectors. In chronic AMR they will need to reduce the inflammatory response induced by donor specific antibodies. New drugs are available and transplant physicians are starting to develop effective multidrug strategies to counter the complex disease mechanisms. Safety of these drugs needs to be further explored especially when used together with other potent immunosuppressive drugs.

From bench to bedside: reversing established antibody responses and desensitization.

Basic transplant immunology has primarily focused on the definition of mechanisms, but an often-stated aspirational goal is to translate basic mechanistic research into future therapy. Pretransplant donor-specific antibodies (DSA) mediate hyperacute as well as early antibody-mediated rejection (AMR), whereas DSA developing late posttransplantation may additionally mediate chronic rejection. Although contemporary immunosuppression effectively prevents early cellular rejection after transplant in nonsensitized patients, it is less effective at controlling preexisting HLA antibody responses or reversing DSA once established, thus underscoring a need for better therapies. We here review the development of a bench-to-bedside approach involving transient proteasome inhibition to deplete plasma cells, combined with maintenance co-stimulation blockade, with CTLA-4Ig or belatacept, to prevent the generation of new antibody-secreting cells (ASCs). This review discusses how this treatment regimen, which was rationally designed and validated to reverse established DSA responses in mouse models, translated into reversing active AMR in the clinic, as well as desensitizing highly sensitized patients on the transplant waitlist.

Plasma cell but not CD20-mediated B-cell depletion protects from bleomycin-induced lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with chronic inflammation and tissue remodelling leading to fibrosis, reduced pulmonary function, respiratory failure and death. Bleomycin (Blm)-induced lung fibrosis in mice replicates several clinical features of human IPF, including prominent lymphoid aggregates of predominantly B-cells that accumulate in the lung adjacent to areas of active fibrosis. We have shown previously a requirement for B-cells in the development of Blm-induced lung fibrosis in mice. To determine the therapeutic potential of inhibiting B-cell function in pulmonary fibrosis, we examined the effects of anti-CD20 B-cell ablation therapy to selectively remove mature B-cells from the immune system and inhibit Blm-induced lung fibrosis. Anti-CD20 B-cell ablation did not reduce fibrosis in this model; however, immune phenotyping of peripheral blood and lung resident cells revealed that anti-CD20-treated mice retained a high frequency of CD19+ CD138+ plasma cells. Interestingly, high levels of CD138+ cells were also identified in the lung tissue of patients with IPF, consistent with the mouse model. Treatment of mice with bortezomib, which depletes plasma cells, reduced the level of Blm-induced lung fibrosis, implicating plasma cells as important effector cells in the development and progression of pulmonary fibrosis.

Kinetics of humoral immunodeficiency with bispecific antibody therapy in multiple myeloma.

8049 Background: Bispecific antibodies (bsAb) are a promising class of therapeutics in RRMM. While hypogammaglobinemia (HGG) is anticipated due to plasma cell depletion, there is a lack of information about the degree of secondary immunodeficiency and resultant infectious complications. We investigated the kinetics of HGG in patients with RRMM on bsAb therapy. Methods: We identified and followed 42 patients treated on early clinical trials of bsAb at our institution between 2019 and 2021. Serial immunoglobulin levels and infections were obtained from the start of therapy until last follow up or 3 months after study exit. Results: 49 treatment courses were included from 42 individual patients. All patients were triple class exposed with a median of 5 prior lines of therapy. The median age was 67 (44-85) years, with 49% females. African Americans accounted for 18% of patients. 96% of patients had at least one prior ASCT. 90% of patients received bsAb targeting BCMA including 7 patients who received more than one line of BCMA targeting therapies. At a median follow up 9.5 (0.9-28.6) months, 40.8% of patients remained on bsAb therapy. At the start of therapy, the median IgG, IgA, and IgM levels were 560 (44-9436), 15 (5-3886) and 6 (5-64) mg/dL, respectively and 50% of patients had severe HGG (≤400mg/dl). Serum IgG levels reached a nadir at 3 months while, IgA and IgM at 1 month, from the start of therapy. The median nadir levels of IgG were 159 (40-2996) mg/dL, while it was &lt; 5 mg/dL for both IgA and IgM. IgG levels were below the detectable range ( &lt; 40 mg/dl) in 28% of patients at some point during therapy. IgA and IgM were also below the detectable range ( &lt; 5 mg/dl) in 50% and 60% of patients, respectively. At last follow-up, the median IgG levels were 444 (40-1860) mg/dL and IgA 5 (5-254) mg/dL and IgM 5 (5-44) mg/dL. Additionally, 38% of patients remained severely hypogammaglobinemic. 57% (24/42) of patients received IVIG supplements in the current series. About 71% of patients had at least one infectious event and the cumulative incidence of infections progressively increased with increasing duration of therapy with risk at 3, 6, 9 12, 15 months being 41%, 57%, 64%, 67% and 70%, respectively. Among these, 54% of infection were bacterial. Viral infection accounted for 41% of infections. A third of patients had new infectious events during the first 90 days following stopping bsAb treatment. 57% (8/14) of patients did not mount a response to the primary COVID19 immunization series. Among the five patients with repeat antibody titers after the booster dose, 50% were still not able to mount an antibody response. Conclusions: bsAb therapy in RRMM can be associated with profound and prolonged HGG. The cumulative risk of infection correlated with the degree of HGG and progressively increases with treatment and persisted months after being off therapy. Additionally, an impaired antibody response to the COVID-19 immunization series was also noted.