Clinical Results with a B Cell Activating Anti-CD73 Antibody for the Immunotherapy of COVID-19

ABSTRACTRobust polyclonal humoral immune responses have the potential to generate a diverse set of antibodies to neutralize and eliminate viruses such as SARS-CoV-2 and protect against transmission, re-infection and the evolution of variants that evade immunity. CD73 is present on subsets of human B and T cells where it plays a role in lymphocyte activation and migration. CD73 also functions as an ectoenzyme that converts AMP into immunosuppressive adenosine. We have developed a humanized anti-CD73 antibody, mupadolimab (CPI-006), that blocks CD73 enzymatic activity and activates CD73POS B cells, thereby inducing differentiation into plasmablasts, immunoglobulin class switching, and antibody secretion independent of the adenosine modulatory activity. These effects suggest mupadolimab may enhance the magnitude, diversity, and duration of anti-viral responses in patients with COVID-19. This hypothesis was tested in a dose escalation phase 1 trial in 29 hospitalized patients with COVID-19. Single doses of 0.3 mg/kg – 5 mg/kg mupadolimab were well tolerated with no drug related adverse events. Doses greater than 0.3 mg/kg resulted in rapid generation of IgG and IgM to SARS-CoV-2 significantly above titers measured in convalescent controls, with elevated IgG titers sustained for more than 6 months beyond presentation of symptoms. Based on these findings, a randomized double-blind, placebo-controlled Phase 3 study in hospitalized patients was initiated. The primary endpoint was proportion of patients alive and free from respiratory failure within 28 days. This trial was discontinued early during the period of waning COVID-19 incidence after enrolling 40 patients. Although underpowered, results from this trial suggest improvement in the primary and key secondary endpoints in patients treated with single doses of 2 mg/kg and 1 mg/kg compared to placebo. The presumed mechanism of action, stimulation of B cells, may represent a novel approach to immunotherapy of COVID-19 and other viral infections.

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A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity

Science Translational Medicine ◽

10.1126/scitranslmed.aar6584 ◽

2019 ◽

Vol 11 (489) ◽

pp. eaar6584 ◽

Cited By ~ 21

Author(s):

Jodi L. Karnell ◽

Marius Albulescu ◽

Stacey Drabic ◽

Liangwei Wang ◽

Rachel Moate ◽

...

Keyword(s):

B Cells ◽

Disease Activity ◽

Plasma Cell ◽

Cell Activation ◽

Phase 1 ◽

Clinical Results ◽

Gene Signature ◽

Induce Platelet Aggregation ◽

Humoral Immune ◽

Dose Dependent

The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67+ dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.

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A crucial role for Jagunal homolog 1 in humoral immunity and antibody glycosylation in mice and humans

Journal of Experimental Medicine ◽

10.1084/jem.20200559 ◽

2020 ◽

Vol 218 (1) ◽

Author(s):

Astrid Hagelkruys ◽

Gerald Wirnsberger ◽

Johannes Stadlmann ◽

Miriam Wöhner ◽

Marion Horrer ◽

...

Keyword(s):

Immune Response ◽

Endoplasmic Reticulum ◽

B Cells ◽

Er Stress ◽

Rare Disease ◽

Humoral Immunity ◽

Viral Infections ◽

Loss Of Function ◽

Humoral Immune ◽

Specific Antigens

Jagunal homolog 1 (JAGN1) has been identified as a critical regulator of neutrophil biology in mutant mice and rare-disease patients carrying JAGN1 mutations. Here, we report that Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) of antibody-producing cells as well as decreased antibody production and secretion. Consequently, mice lacking Jagn1 in B cells exhibit reduced serum immunoglobulin (Ig) levels at steady state and fail to mount an efficient humoral immune response upon immunization with specific antigens or when challenged with viral infections. We also demonstrate that Jagn1 deficiency in B cells results in aberrant IgG N-glycosylation leading to enhanced Fc receptor binding. Jagn1 deficiency in particular affects fucosylation of IgG subtypes in mice as well as rare-disease patients with loss-of-function mutations in JAGN1. Moreover, we show that ER stress affects antibody glycosylation. Our data uncover a novel and key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.

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Antibody-independent functions of B cells during viral infections

PLoS Pathogens ◽

10.1371/journal.ppat.1009708 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009708

Author(s):

Vinit Upasani ◽

Izabela Rodenhuis-Zybert ◽

Tineke Cantaert

Keyword(s):

B Cells ◽

B Cell ◽

Antigen Presentation ◽

Cytokine Production ◽

Viral Infections ◽

Cell Receptor ◽

Humoral Immune ◽

Cell Functions ◽

Chronic Viral Infections ◽

Independent Functions

The humoral immune response and antibody-mediated functions of B cells during viral infections are well described. However, we have limited understanding of antibody-independent B cell functions, such as cytokine production and antigen presentation, in acute and chronic viral infections and their role in protection and/or immunopathogenesis. Here, we summarize the current literature on these antibody-independent B cell functions and identify remaining knowledge gaps. B cell subsets produce anti- and pro-inflammatory cytokines, which can have both beneficial and detrimental effects during viral clearance. As professional antigen presenting cells, B cells also play an important role in immune regulation/shaping of the developing adaptive immune responses. Since B cells primarily express TLR7 and TLR9, we specifically discuss the role of Toll-like receptor (TLR)-mediated B cell responses to viral infections and their role in augmenting adaptive immunity through enhanced cytokine production and antigen presentation. However, viruses have evolved strategies to subvert TLR signaling and additional stimulation via B cell receptor (BCR) may be required to overcome the defective TLR response in B cells. To conclude, antibody-independent B cell functions seem to have an important role in regulating both acute and chronic viral infections and may form the basis for novel therapeutic approaches in treatment of viral infections in the future.

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A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with rituximab for previously treated indolent non-Hodgkin lymphomas (iNHL).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps8617 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS8617-TPS8617 ◽

Cited By ~ 1

Author(s):

John Leonard ◽

Pier Luigi Zinzani ◽

Wojciech Jurczak ◽

Mathias J. Rummel ◽

Gilles A. Salles ◽

...

Keyword(s):

B Cells ◽

Primary Endpoint ◽

Phase 1 ◽

Phase Iii ◽

Controlled Study ◽

Rank Test ◽

Lymphoid Tissues ◽

Tumor Type ◽

Double Blind ◽

Previously Treated

TPS8617 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Phase 1 trials demonstrated that idelalisib is highly active in pts with heavily pretreated iNHL: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with acceptable safety profile (de Vos et al, 2011). Methods: 375 pts with previously treated iNHL, who have measurable lymphadenopathy, have received prior anti-CD20-antibody-containing therapy, and who have iNHL that is not refractory to rituximab (R) are randomized in a 2:1 ratio into Arm A or Arm B. In Arm A, pts receive idelalisib at 150 mg BID continuously + R at 375 mg/m2 (weekly x 4 then every 8 weeks x 4). In Arm B, pts receive placebo BID instead of idelalisib. Stratification factors include tumor type (follicular lymphoma vs others), tumor burden (high vs low), and time since completion of last prior therapy for iNHL (<18 months vs ≥18 months). The primary endpoint is PFS and key secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Dec 2012 (NCT01732913). Clinical trial information: NCT01732913.

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