A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins

doi:10.1016/j.clim.2016.02.009

Clinical Immunology

Volume 165, April 2016, Pages 55-59

https://doi.org/10.1016/j.clim.2016.02.009 Get rights and content

Highlights

•
Antibodies to life saving therapeutic proteins such as enzyme replacement therapies for lysosomal storage diseases may inhibit product efficacy leading to clinical deterioration and death, as in the case of Pompe Disease.
•
Autoantibodies may mediate pathology in the context of certain autoimmune diseases.
•
High titer, sustained antibody responses may not diminish in response to treatment with immune suppressive agents such as rituximab, methotrexate or cytoxan. Such responses appear to be mediated by long lived plasma cells which are not targeted by B cell targeting mAbs and resistant to many chemotherapeutic agents
•
High titer sustained antibody responses in the context of autoimmune disease or immune responses to therapeutic proteins refractory to treatment with conventional immune suppressive agents have been dramatically diminished or eliminated by treatment of patients with bortezomib, a proteasome inhibitor, facilitating restoration of immune tolerance.
•
In view of these findings, larger scale studies of proteasome inhibitors in the context of autoimmune disease mediated by robust autoantibody responses should be pursued.

Abstract

Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology.

Section snippets

Plasma cell targeting agents

Given the considerations above, we believe that it is appropriate to investigate the safety and efficacy of plasma cell targeting agents in larger scale clinical trials that are sufficiently powered to delineate the risks and benefits of such therapies in antibody-mediated clinical conditions. Drugs used to treat multiple myeloma, a plasma cell malignancy characterized by proliferation and accumulation of abnormal plasma cells, may provide clues for drugs that could potentially be explored for

From diminished antibody response to immune tolerance induction

It should also be noted that reversal of long standing antibody or autoantibody responses may not be sufficient to achieve the ultimate goal of immune tolerance induction defined as the lack of a significant immune response in the face of continued treatment with the therapeutic protein, or ongoing exposure to self-antigen in the setting of autoimmune disease, without concomitant immune suppressive agents, conferring long term freedom from treatment with immune suppressive agents. For example,

Conclusions

Recent case reports and small case series in which bortezomib has been targeted to pathological antibody responses in several clinical scenarios have provided evidence of clinical improvement in some patients. Such results provide a strong incentive to perform larger scale clinical trials to evaluate the potential efficacy and safety of agents targeting long-lived plasma cells as a component of immune tolerizing regimens for patients with robust antibody responses to therapeutic proteins and in

Disclaimer

The views expressed in this manuscript represent the opinions of the authors, and do not necessarily represent the official views of the FDA.

References (45)

J. Van der Vlag et al.
Lupus nephritis: role of antinucleosome autoantibodies
Semin. Nephrol.
(2011)
S.G. Banugaria et al.
The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease
Genet. Med.
(2011)
J.M. De Vries et al.
High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa
Mol. Genet. Metab.
(2010)
P.S. Kishnani et al.
Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants
Mol. Genet. Metab.
(2010)
H. Zhao et al.
Enzyme therapy of Gaucher disease: clinical and biochemical changes during production of and tolerization for neutralizing antibodies
Blood Cells Mol. Dis.
(2003)
E. Ponce et al.
Grabowski G/enzyme therapy in Gaucher disease type 1: effect of neutralizing antibodies to acid beta-glucosidase
Blood
(1997)
Y.H. Messinger et al.
Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease
Genet. Med.
(2012)
M. Basler et al.
The immunoproteasome in antigen processing and other immunological functions
Curr. Opin. Immunol.
(2013)
Y. Wang et al.
Successful treatment of warm type haemolytic anemia with bortezomib in a rituximab-failed systemic lupus erythematosus patient
Rheumatology (Oxford)
(2015)
B.A. Teicher et al.
Proteasome inhibitors
Biochem. Pharmacol.
(2015)

D. DiMichele

Immune tolerance therapy for factor VIII inhibitors: moving from empiricism to an evidence-based approach

J. Thromb. Haemost.

(2007)

C.L. Bennett

Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up. Report from the Research on Adverse Drug Events and Reports (RADAR) Project

Blood

(2005)

J. Shortt et al.

ADAMTS13 antibody depletion by bortezomib in thrombotic thrombocytopenic purpura

N. Engl. J. Med.

(2013)

S.G. Banugaria et al.

Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic proteins: lessons learned from Pompe disease

Genet. Med.

(2012)

A.M. Gomez et al.

Targeting plasma cells with proteasome inhibitors: possible roles in treating myasthenia gravis?

Ann. N. Y. Acad. Sci.

(2012)

Z. Paz et al.

New therapeutics in systemic lupus erythematosus

Curr. Opin. Rheumatol.

(2013)

M. Sem et al.

Rituximab treatment of the anti-synthetase syndrome—a retrospective case series

Rheumatology

(2009)

S. Leth et al.

Autoimmune pulmonary alveolar proteinosis: treatment options in the year 2013

Respirology

(2013)

C. Hanrotel-Saliou et al.

Glomerular antibodies in lupus nephritis

Clin. Rev. Allergy Immunol.

(2011)

S. Yung et al.

Anti-DNA antibodies in the pathogenesis of lupus nephritis—the emerging mechanisms

Autoimmun. Rev.

(2008)

T. Gono et al.

Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus

Rheumatology (Oxford)

(2011)

M.B. Lauvsnes et al.

Systemic lupus erythematosus, the brain, and anti-NR2 antibodies

J. Neurol.

(2012)

Cited by (18)

Emerging approaches to induce immune tolerance to therapeutic proteins
2023, Trends in Pharmacological Sciences
Immunogenicity affects the safety and efficacy of therapeutic proteins. This review is focused on approaches for inducing immunological tolerance to circumvent the immunogenicity of therapeutic proteins in the clinic. The few immune tolerance strategies that are used in the clinic tend to be inefficient and expensive and typically involve global immunosuppression, putting patients at risk of infections. The hallmark of a desirable immune tolerance regimen is the specific alleviation of immune responses to the therapeutic protein. In the past decade, proof-of-principle studies have demonstrated that emerging technologies, including nanoparticle-based delivery of immunomodulators, cellular targeting and depletion, cellular engineering, gene therapy, and gene editing, can be leveraged to promote tolerance to therapeutic proteins. We discuss the potential of these novel approaches and the barriers that need to be overcome for translation into the clinic.
P2Y<inf>2</inf> receptor antagonism resolves sialadenitis and improves salivary flow in a Sjögren's syndrome mouse model
2021, Archives of Oral Biology
Citation Excerpt :
Despite the body of evidence implicating B cells in SS pathogenesis, B cell depletion using Rituximab has been largely ineffective as a therapeutic strategy (Letaief et al., 2018), possibly due to co-depletion of anti-inflammatory B regulatory cells that are elevated in human SS patients (Mielle et al., 2019). Another explanation for the lack of Rituximab efficacy may be that it fails to deplete long-lived plasma cells (Mahevas, Michel, Weill, & Reynaud, 2013; Rosenberg et al., 2016). The exciting in vivo findings that both P2X7R (Khalafalla et al., 2017) and P2Y2R antagonism (shown here) ameliorate SS-related hyposalivation and resolve lymphocytic infiltration in the salivary glands of NOD.H-2h4 DKO mice support targeting the ATP-P2X7R-P2Y2R axis as a therapeutic strategy for the treatment of SS in humans.
Sjögren’s syndrome (SS) is a chronic autoimmune exocrinopathy characterized by lymphocytic infiltration of the salivary and lacrimal glands and decreased saliva and tear production. Previous studies indicate that the G protein-coupled P2Y₂ nucleotide receptor (P2Y₂R) is upregulated in numerous models of salivary gland inflammation (i.e., sialadenitis), where it has been implicated as a key mediator of chronic inflammation. Here, we evaluate both systemic and localized P2Y₂R antagonism as a means to resolve sialadenitis in the NOD.H-2^h4,IFNγ^−/−,CD28^−/− (NOD.H-2^h4 DKO) mouse model of SS.
Female 4.5 month old NOD.H-2^h4 DKO mice received daily intraperitoneal injections for 10 days of the selective P2Y₂R antagonist, AR-C118925, or vehicle-only control. Single-dose localized intraglandular antagonist delivery into the Wharton’s duct was also evaluated. Carbachol-induced saliva was measured and then submandibular glands (SMGs) were isolated and either fixed and paraffin-embedded for H&E staining, homogenized for RNA isolation or dissociated for flow cytometry analysis.
Intraperitoneal injection, but not localized intraglandular administration, of AR-C118925 significantly enhanced carbachol-induced salivation and reduced lymphocytic foci and immune cell markers in SMGs of 5 month old NOD.H-2^h4 DKO mice, compared to vehicle-injected control mice. We found that B cells represent the primary immune cell population in inflamed SMGs of NOD.H-2^h4 DKO mice that express elevated levels of P2Y₂R compared to C57BL/6 control mice. We further demonstrate a role for P2Y₂Rs in mediating B cell migration and the release of IgM.
Our findings suggest that the P2Y₂R represents a novel therapeutic target for the treatment of Sjögren’s syndrome.
Multi-omics Data Analyses Construct TME and Identify the Immune-Related Prognosis Signatures in Human LUAD
2020, Molecular Therapy Nucleic Acids
Citation Excerpt :
Then, the immune content of each sample was dissected into 22 types of immune cell members. The high-immunity cohort had significantly larger fractions of memory B cells, CD8 T cells, activated memory CD4 T cells, M1 macrophages, resting dendritic cells, activated mast cells, and gamma delta T cells and smaller fractions of plasma cells, M0 macrophages, and activated dendritic cells (Mann-Whitney U test, p < 0.05) (Figure 1G), which is consistent with the proposed anti-immune or pro-immune functions of these cell members.23–28 Of note, some of these immune cell members have potential correlations, such as the positive correlation of activated dendritic cells on CD8 T cell infiltration in lung cancer.29
Lung cancer has been the focus of attention for many researchers in recent years for the leading contribution to cancer-related death worldwide, in which lung adenocarcinoma (LUAD) is the most common histological type. However, the potential mechanism behind LUAD initiation and progression remains unclear. Aiming to dissect the tumor microenvironment of LUAD and to discover more informative prognosis signatures, we investigated the immune-related differences in three types of genetic or epigenetic characteristics (expression status, somatic mutation, and DNA methylation) and considered the potential roles that these alterations have in the immune response and both the immune-related metabolic and neural systems by analyzing the multi-omics data from The Cancer Genome Atlas (TCGA) portal. Additionally, a four-step strategy based on lasso regression and Cox regression was used to construct the prognostic prediction model. For the prognostic predictions on the independent test set, the performance of the trained models (average concordance index [C-index] = 0.839) is satisfied, with average 1-year, 3-year, and 5-year areas under the curve (AUCs) equal to 0.796, 0.786, and 0.777. Finally, the overall model was constructed based on all samples, which comprised 27 variables and achieved a high degree of accuracy on the 1-year (AUC = 0.861), 3-year (AUC = 0.850), and 5-year (AUC = 0.916) survival predictions.
Catalytic bioscavengers as countermeasures against organophosphate nerve agents
2018, Chemico-Biological Interactions
Citation Excerpt :
This problem is likely to increase with repeated dosing and can render the drug ineffective and perhaps harmful. On the other hand, the administration of large doses of human enzymes may elicit an autoimmune response that may lead to the inactivation of both the exogenously introduced and endogenously generated enzyme [249] [10]. In spite of the complicating factors described above, the past 40 years has seen an increasing application of protein drugs such as: antibodies, fusion proteins and enzymes in the treatment of a wide range of human diseases.
Recent years have seen an increasing number of incidence, in which organophosphate nerve agents (OPNAs) have been used against civilians with devastating outcomes. Current medical countermeasures against OPNA intoxications are aimed at mitigating their symptoms, but are unable to effectively prevent them. In addition, they may fail to prevent the onset of a cholinergic crisis in the brain and its secondary toxic manifestations. The need for improved medical countermeasures has led to the development of bioscavengers; proteins and enzymes that may prevent intoxication by binding and inactivating OPNAs before they can reach their target organs. Non-catalytic bioscavengers such as butyrylcholinesterase, can rapidly bind OPNA molecules in a stoichiometric and irreversible manner, but require the administration of large protein doses to prevent intoxication. Thus, many efforts have been made to develop catalytic bioscavengers that could rapidly detoxify OPNAs without being inactivated in the process. Such enzymes may provide effective prophylactic protection and improve post-exposure treatments using much lower protein doses. Here we review attempts to develop catalytic bioscavengers using molecular biology, directed evolution and enzyme engineering techniques; and natural or computationally designed enzymes. These include both stoichiometric scavengers and enzymes that can hydrolyze OPNAs with low catalytic efficiencies. We discuss the catalytic parameters of evolved and engineered enzymes and the results of in-vivo protection and post-exposure experiments performed using OPNAs and bioscavengers. Finally, we briefly address some of the challenges that need to be met in order to transition these enzymes into clinically approved drugs.
Could daratumumab be used to treat severe allergy?
2017, Journal of Allergy and Clinical Immunology
Advancing pharmaceutical quality: An overview of science and research in the U.S. FDA's Office of Pharmaceutical Quality
2016, International Journal of Pharmaceutics
Citation Excerpt :
With respect to medical interventions, there is a desire to modulate pathological antibody response, for example in patients with adverse responses to therapeutic proteins or autoimmune diseases. FDA scientists hypothesized that targeting long-lived plasma cells may result in immune tolerization in several clinical scenarios (Rosenberg et al., 2016). This concept was supported by recent studies of immune tolerance to enzyme replacement therapies (Kazi et al., 2016).
Failures surrounding pharmaceutical quality, particularly with respect to product manufacturing issues and facility remediation, account for the majority of drug shortages and product recalls in the United States. Major scientific advancements pressure established regulatory paradigms, especially in the areas of biosimilars, precision medicine, combination products, emerging manufacturing technologies, and the use of real-world data. Pharmaceutical manufacturing is increasingly globalized, prompting the need for more efficient surveillance systems for monitoring product quality. Furthermore, increasing scrutiny and accelerated approval pathways provide a driving force to be even more efficient with limited regulatory resources. To address these regulatory challenges, the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA) harbors a rigorous science and research program in core areas that support drug quality review, inspection, surveillance, standards, and policy development. Science and research is the foundation of risk-based quality assessment of new drugs, generic drugs, over-the-counter drugs, and biotechnology products including biosimilars. This is an overview of the science and research activities in OPQ that support the mission of ensuring that safe, effective, and high-quality drugs are available to the American public.

View all citing articles on Scopus

View full text

Review ArticleA role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins

Highlights

Abstract

Section snippets

Plasma cell targeting agents

From diminished antibody response to immune tolerance induction

Conclusions

Disclaimer

Semin. Nephrol.

Genet. Med.

Mol. Genet. Metab.

Mol. Genet. Metab.

Blood Cells Mol. Dis.

Blood

Genet. Med.

Curr. Opin. Immunol.

Rheumatology (Oxford)

Biochem. Pharmacol.

J. Thromb. Haemost.

Blood

ADAMTS13 antibody depletion by bortezomib in thrombotic thrombocytopenic purpura

N. Engl. J. Med.

Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic proteins: lessons learned from Pompe disease

Genet. Med.

Targeting plasma cells with proteasome inhibitors: possible roles in treating myasthenia gravis?

Ann. N. Y. Acad. Sci.

New therapeutics in systemic lupus erythematosus

Curr. Opin. Rheumatol.

Rituximab treatment of the anti-synthetase syndrome—a retrospective case series

Rheumatology

Autoimmune pulmonary alveolar proteinosis: treatment options in the year 2013

Respirology

Glomerular antibodies in lupus nephritis

Clin. Rev. Allergy Immunol.

Anti-DNA antibodies in the pathogenesis of lupus nephritis—the emerging mechanisms

Autoimmun. Rev.

Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus

Rheumatology (Oxford)

Systemic lupus erythematosus, the brain, and anti-NR2 antibodies

J. Neurol.

Review Article
A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins