Pros and Cons of the Immunogenicity of Monoclonal Antibodies in Cancer Treatment: A Lesson from Autoimmune Diseases

Talotta, Rossella; Rucci, Francesco; Canti, Gianfranco; Scaglione, Francesco

doi:10.2217/imt-2018-0081

Cited by 25 publications

(24 citation statements)

References 75 publications

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“…The immunogenicity of BD relies on the state of the disease. In autoimmune disorders, the hyperactivation of both the innate and adaptive immune system may augment the risk for immunogenic drugs to stimulate an immune response; for example, antidrug antibodies are more commonly detected in rheumatic than neoplastic diseases . We defined renal involvement, frequent hospitalizations (>14 times/lifetime), and more than two different BD used as risk factors for development of immediate BD hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Severe hypersensitivity reactions to biological drugs in children with rheumatic diseases

Soyer

Bilginer

Batu

et al. 2019

Pediatric Allergy Immunology

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Background: Hypersensitivity reactions (HSR) to biologic drugs (BD) may limit their use in children with rheumatic diseases. We aimed to analyze the incidence and clinical characteristics of immediate type I (IgE/non-IgE) hypersensitivity reactions to BD and the risk factors for these reactions.Methods: Children with rheumatic diseases using BD who were evaluated in the pediatric allergy department for possible drug hypersensitivity reaction (DHR) due to BD or any other drug were included in the study. Results: One hundred and twenty-eight children (49.2% boys; 14.6 years [9.9-16.9 years] with juvenile idiopathic arthritis [58%], familial Mediterranean fever [14%], vasculitis [14%], and other diseases [14%]) had used eight different BD with 32 494 infusions/injections. Fifteen patients were evaluated for DHR [injection-site reactions [n = 4], adverse events [n = 2], drug hypersensitivity other than BD [n = 3],and immediate BD hypersensitivity [n = 6]). The incidence of immediate BD HSR was 4.7%, with a clinical presentation of anaphylaxis in 3.9% (tocilizumab [n = 3], rituximab [n = 2], positive skin test with culprit BD [n = 3]). Among patients with BD HSR, the median follow-up was longer (84.5 vs 54 months, P = .048), and renal (33.3% vs 4.1%, P = .002), hematologic involvement (16.7% vs 0, P < .001), and active disease (83.3% vs 13.9%, P < .001) were more common. Logistic regression analysis revealed that renal involvement, more than 14 hospitalizations per lifetime, and more than two different BD used were associated with BD hypersensitivity. Conclusion:The frequency of severe immediate HSR due to BD was shown to be 3.9% in children with rheumatic diseases. Children with active rheumatic disease and who have exposure to multiple BD should be monitored for BD HSR, particularly during intravenous BD infusions. K E Y W O R D Sbiologic drugs, children, hypersensitivity, rheumatic diseases

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Section: Discussionmentioning

confidence: 99%

Severe hypersensitivity reactions to biological drugs in children with rheumatic diseases

Soyer

Bilginer

Batu

et al. 2019

Pediatric Allergy Immunology

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“…In the T-cell dependent pathway, mAbs act as antigens and are internalized by antigen presenting cells (APCs), processed, and presented to T cells via the cognate interaction between the MHC class II molecules and T-cell receptor. Depending on the cytokine milieu during this interaction, several different immune responses can occur ( 57 ). In the T-cell dependent pathway, ADAs are generated when a T helper cell (Th) differentiates into a Th1 or Th2 phenotype and, following their cognate interactions with B cells, induces the proliferation of plasma cells (PC) that secrete ADAs.…”

Section: The Molecular Mechanisms That Lead To Ada Formationmentioning

confidence: 99%

“…The extent of immunogenicity thus differs among patients receiving the same mAb, which could be related to the immune pathways underlying the pathogenesis of the disease ( 71 ). For example, RA patients have a higher likelihood of developing ADAs toward a mAb drug than spondyloarthritis patients ( 57 ). When examining a specific disease or immune target, different mAbs may have a varying effect on the induction of ADAs.…”

Section: Drug and Patient Characteristics Contributing To Ada Formatimentioning

confidence: 99%

The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment With Monoclonal Antibodies

et al. 2020

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Monoclonal antibodies (mAbs) are a crucial asset for human health and modern medicine, however, the repeated administration of mAbs can be highly immunogenic. Drug immunogenicity manifests in the generation of anti-drug antibodies (ADAs), and some mAbs show immunogenicity in up to 70% of patients. ADAs can alter a drug’s pharmacokinetic and pharmacodynamic properties, reducing drug efficacy. In more severe cases, ADAs can neutralize the drug’s therapeutic effects or cause severe adverse events to the patient. While some contributing factors to ADA formation are known, the molecular mechanisms of how therapeutic mAbs elicit ADAs are not completely clear. Accurate ADA detection is necessary to provide clinicians with sufficient information for patient monitoring and clinical intervention. However, ADA assays present unique challenges because both the analyte and antigen are antibodies, so most assays are cumbersome, costly, time consuming, and lack standardization. This review will discuss aspects related to ADA formation following mAb drug administration. First, we will provide an overview of the prevalence of ADA formation and the available diagnostic tools for their detection. Next, we will review studies that support possible molecular mechanisms causing the formation of ADA. Finally, we will summarize recent approaches used to decrease the propensity of mAbs to induce ADAs.

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“…Protein-based drugs administered to patients may induce humoral immune responses, causing the development of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) during repeated infusions. 15 Besides neutralizing therapeutic effects, immunogenicity can also cause life-threatening complications, such as anaphylaxis and immune complexmediated disease. 16,17 For these reasons, it is important to study the incidence of immunogenicity in patients treated with anti-PD-1 mAbs in clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit

Wang¹,

Fei²,

Hua³

et al. 2019

mAbs

109

101

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Blockade of immune checkpoint pathways by programmed cell death protein 1 (PD-1) antibodies has demonstrated broad clinical efficacy against a variety of malignancies. Sintilimab, a highly selective, fully human monoclonal antibody (mAb), blocks the interaction of PD-1 and its ligands and has demonstrated clinical benefit in various clinical studies. Here, we evaluated the affinity of sintilimab to human PD-1 by surface plasmon resonance and mesoscale discovery and evaluated PD-1 receptor occupancy and anti-tumor efficacy of sintilimab in a humanized NOD/Shi-scid-IL2rgamma (null) (NOG) mouse model. We also assessed the receptor occupancy and immunogenicity of sintilimab from clinical studies in humans (9 patients with advanced solid tumor and 381 patients from 4 clinical studies, respectively). Sintilimab bound to human PD-1 with greater affinity than nivolumab (Opdivo®, MDX-1106) and pembrolizumab (Keytruda®, MK-3475). The high affinity of sintilimab is explained by its distinct structural binding mode to PD-1. The pharmacokinetic behavior of sintilimab did not show any significant differences compared to the other two anti-PD-1 mAbs. In the humanized NOG mouse model, sintilimab showed superior PD-1 occupancy on circulating T cells and a stronger anti-tumor effect against NCI-H292 tumors. The strong anti-tumor response correlated with increased interferon-γ-secreting, tumor-specific CD8+ T cells, but not with CD4+ Tregs in tumor tissue. Pharmacodynamics testing indicated a sustained mean occupancy of ≥95% of PD-1 molecules on circulating T cells in patients following sintilimab infusion, regardless of infusion dose. Sintilimab infusion was associated with 0.52% (2/381 patients) of anti-drug antibodies and 0.26% (1/381 patients) neutralizing antibodies. These data validate sintilimab as a novel, safe, and efficacious anti-PD-1 mAb for cancer immunotherapy.

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Pros and Cons of the Immunogenicity of Monoclonal Antibodies in Cancer Treatment: A Lesson from Autoimmune Diseases

Cited by 25 publications

References 75 publications

Severe hypersensitivity reactions to biological drugs in children with rheumatic diseases

Severe hypersensitivity reactions to biological drugs in children with rheumatic diseases

The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment With Monoclonal Antibodies

Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit

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