Immediate adverse reactions to biologicals: from pathogenic mechanisms to prophylactic management

Vultaggio, Alessandra; Maggi, Enrico; Matucci, Andrea

doi:10.1097/aci.0b013e3283464bcd

Cited by 63 publications

(52 citation statements)

References 57 publications

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“…with pOVA developed anaphylactoid responses after three weekly i.v. infusions of pOVA, reminiscent of the antibody-mediated hypersensitivity reactions observed in some patients who develop antidrug antibodies (35)(36)(37). Untreated animals with high titers against OVA from Fig.…”

Section: Resultsmentioning

confidence: 97%

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Maldonado

LaMothe

Ferrari

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

379

423

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Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.U ndesired immunogenicity can have a profound impact on human health. Allergies, including allergic asthma and severe food allergies, affect ∼20% of the population, and the prevalence has been steadily increasing over the past several decades (1). The prevalence of autoimmune diseases, including multiple sclerosis and type 1 diabetes, is ∼4.5% (2). Unwanted immunogenicity can also affect both efficacy and safety of biologic drugs (3), particularly in the case of protein replacement therapies for the treatment of genetic deficiencies, such as hemophilia A (4) and Pompe Disease (5). Immunomodulatory agents commonly used to control immunogenicity are often broadly immunosuppressive and typically require chronic administration that can lead to reactivation of latent pathogens, development of tumors, and opportunistic infections (6, 7). Therefore, antigen-specific, durable tolerogenic therapy would be highly desirable from an efficacy and safety perspective.Multiple techniques for antigen-specific immunotherapy have been described, although only allergen immunotherapy, wherein low doses of antigen are delivered in the absence of immunomodulating agents, is currently used in the clinic (1). Experimental approaches have included oral administration of antigen, high dose tolerance, and the use of altered peptide ligands (8). Although these methods have been successful in preclinical models, translation to human clinical trials has been largely disappointing (8). Alternative strategies to leverage tolerogenic programming associated with apoptotic cells include conjugating antigen to splenocytes (9-12) or synthetic microparticles (13, 14) or targeting antigen to the surface of red blood cells (15). Other approaches include loading particles with MHC complexes that present relevant peptides i...

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Section: Resultsmentioning

confidence: 97%

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Maldonado

LaMothe

Ferrari

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

379

423

View full text Add to dashboard Cite

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“…They may be difficult to distinguish from type I hypersensitivity reactions, which typically occur at mAb re-exposure. 34 For mAbs administered via the subcutaneous route, pruritus, erythema, induration, and swelling are relatively common injection-site manifestations that typically appear within minutes to 2 days of administration and are mostly benign and self-limiting with continued therapy. 35 In contrast to the more acute types of modality-related reactions discussed in the previous paragraph, immunogenicity represents a delayed hypersensitivity that occurs in a longer time frame that can have an impact on the therapeutic efficacy of the mAb.…”

Section: Safety Considerationsmentioning

confidence: 99%

“…36 Extrinsic factors also contribute to the development of immune responses such as aggregate formation, adjuvant-like contaminants, administration protocol, comedication, and even the treated disorder. 34 Overall, immune responses are considerably reduced with the use of fully human mAbs; however, there is always a risk of developing anti-antibody responses, even with fully human mAbs.…”

Section: Safety Considerationsmentioning

confidence: 99%

Evolution and Emergence of Therapeutic Monoclonal Antibodies

2013

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“…CTLL-2/ hIL5Rα cells (6×10 4 /well) and NK92/NFAT-luciferase cells (2×10 4 /well) were washed, counted, and added to each well of the plate. The mixture of serum sample, benralizumab, and cells was incubated in a humidified cell culture incubator (37±2°C with 5±1% CO 2 ) for 4.5 h. Steady-Glo ® was added to each well and incubated for 60±5 min at RT.…”

Section: Assay Proceduresmentioning

confidence: 99%

“…Assessing anti-drug antibodies (ADAs) for neutralizing activity is a key characterization step since neutralizing ADAs may lead to altered pharmacokinetic (PK) and pharmacodynamic (PD) profiles (1,2), reduced drug efficacy, and adverse events (3,4).…”

Section: Introductionmentioning

confidence: 99%

A Neutralizing Antibody Assay Based on a Reporter of Antibody-Dependent Cell-Mediated Cytotoxicity

Wu¹,

Li²,

Kim³

et al. 2015

AAPS J

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Abstract. Benralizumab is a humanized anti-IL5 receptor α (IL5Rα) monoclonal antibody (mAb) with enhanced (afucosylation) antibody-dependent cell-mediated cytotoxicity (ADCC) function. An ADCC reporter cell-based neutralizing antibody (NAb) assay was developed and characterized to detect NAb against benralizumab in human serum to support the clinical development of benralizumab. The optimal ratio of target cells to effector cells was 3:1. Neither parental benralizumab (fucosylated) nor benralizumab Fab resulted in ADCC activity, confirming the requirement for ADCC activity in the NAb assay. The serum tolerance of the cells was determined to be 2.5%. The cut point derived from normal and asthma serum samples was comparable. The effective range of benralizumab was determined, and 35 ng/mL [80% maximal effective concentration (EC 80 )] was chosen as the standard concentration to run in the assessment of NAb. An affinity purified goat anti-benralizumab polyclonal idiotype antibody preparation was shown to have NAb since it inhibited ADCC activity in a dosedependent fashion. The low endogenous concentrations of IL5 and soluble IL5 receptor (sIL5R) did not demonstrate to interfere with the assay. The estimated assay sensitivities at the cut point were 1.02 and 1.10 μg/mL as determined by the surrogate neutralizing goat polyclonal and mouse monoclonal anti-drug antibody (ADA) controls, respectively. The assay can detect NAb (at 2.5 μg/mL) in the presence of 0.78 μg/mL benralizumab. The assay was not susceptible to non-specific matrix effects. This study provides an approach and feasibility of developing an ADCC cell-based NAb assay to support biopharmaceuticals with an ADCC function.

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Immediate adverse reactions to biologicals: from pathogenic mechanisms to prophylactic management

Abstract: Considering the increased use of the biological therapies in different clinical conditions, the definition of diagnostic and prophylactic strategies represents an unavoidable necessity in the management of potentially reactive patients in order to improve the safety profile of biologics.

Cited by 63 publications

References 57 publications

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Evolution and Emergence of Therapeutic Monoclonal Antibodies

A Neutralizing Antibody Assay Based on a Reporter of Antibody-Dependent Cell-Mediated Cytotoxicity

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