Cross-reactive and pre-existing antibodies to therapeutic antibodies—Effects on treatment and immunogenicity

Schie, Karin A van; Wolbink, Gertjan; Rispens, Theo

doi:10.1080/19420862.2015.1048411

Cited by 94 publications

(73 citation statements)

References 107 publications

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“…In addition to a potential implication related to treatment-induced ADA detection and risks, pre-existing antibodies may impact the ability to detect the desired drug analyte in the PK assay, or they may directly alter the rate of drug clearance (33,34,40). Specifically, pre-existing antibodies may interfere with the PK assay, leading to under-or overreporting of drug concentration.…”

Section: Management Of Pre-existing Drug-reactive Antibody Risk Impacmentioning

confidence: 99%

“…Pre-existing antibodies that recognize the idiotopes are expected to interfere with target binding when the idiotopes are part of the antigen binding site, or in close proximity to the antigen binding site. These antibodies may lead to drug neutralization, loss of efficacy, and ultimately treatment failure (20,34). Pre-existing antibodies recognizing the allotopes of antibody biotherapeutics are less likely to neutralize the interaction between the biotherapeutic and the target, therefore, less likely to cause rapid clearance of the drug or have major impact on efficacy (35).…”

Section: Pre-existing Antibodies To Antibody-based Biotherapeuticsmentioning

confidence: 99%

See 1 more Smart Citation

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

Xue

Clements-Egan

Amaravadi

et al. 2017

AAPS J

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Abstract.Anti-drug antibodies (ADA) pose a potential risk to patient safety and efficacy and are routinely monitored during clinical trials. Pre-existing drug-reactive antibodies are present in patients without prior drug exposure and are defined by their ability to bind to a component of the drug. These pre-existing drug-reactive antibodies are frequently observed and could represent an adaptive immune response of an individual who has been previously exposed to antigens with structural similarities to the biotherapeutic. Clinical consequences of these antibodies can vary from no impact to adverse effects on patient safety, exposure, and efficacy, and are highly dependent on biotherapeutic modality, disease indications, and patient demographics. This paper describes how the immunogenicity risk assessment of a biotherapeutic integrates the existence of pre-existing drug-reactive antibodies, and provides recommendations for risk-based strategies to evaluate treatment-emergent ADA responses.

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Section: Management Of Pre-existing Drug-reactive Antibody Risk Impacmentioning

confidence: 99%

Section: Pre-existing Antibodies To Antibody-based Biotherapeuticsmentioning

confidence: 99%

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

Xue

Clements-Egan

Amaravadi

et al. 2017

AAPS J

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“…Post-translational modifications of biotherapeutics produced in non-human cell lines may result in generation of glycans uncommon to humans with known antibody specificity. Antibodies specific to various non-human glycans have been broadly reported (Table I) and recently reviewed by Karin et al (14). Anti-Gal-α-1,3-Gal-specific immunoglobulins are naturally present in normal humans at high titers although only the presence of IgE isotype was correlated with allergic reactions to meat or Cetuximab ™ , a biotherapeutic that contains the Gal-α-1,3-Gal on its Fab region (35,36).…”

Section: Nature and Characterization Of Pre-existing Reactivity In Admentioning

confidence: 99%

“…Patients who are positive for pre-Ab and undergo therapy may subsequently experience an adverse clinical event due to hypersensitivity reactions (7)(8)(9). Pre-Abs have been associated with a post-treatment loss of product efficacy and adverse safety consequences (10), as observed with enzyme therapy, TNF-alpha inhibitors, and interferons (11)(12)(13)(14)(15). Other cases have shown no clinical impact (16).…”

Section: Introductionmentioning

confidence: 99%

Pre-existing Antibody: Biotherapeutic Modality-Based Review

Gorovits

Clements-Egan

Birchler

et al. 2016

AAPS J

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Abstract. Pre-existing antibodies to biotherapeutic drugs have been detected in drug-naïve subjects for a variety of biotherapeutic modalities. Pre-existing antibodies are immunoglobulins that are either specific or cross-reacting with a protein or glycan epitopes on a biotherapeutic compound. Although the exact cause for pre-existing antibodies is often unknown, environmental exposures to non-human proteins, glycans, and structurally similar products are frequently proposed as factors. Clinical consequences of the pre-existing antibodies vary from an adverse effect on patient safety to no impact at all and remain highly dependent on the biotherapeutic drug modality and therapeutic indication. As such, pre-existing antibodies are viewed as an immunogenicity risk factor requiring a careful evaluation. Herein, the relationships between biotherapeutic modalities to the nature, prevalence, and clinical consequences of pre-existing antibodies are reviewed. Initial evidence for pre-existing antibody is often identified during anti-drug antibody (ADA) assay development. Other interfering factors known to cause false ADA positive signal, including circulating multimeric drug target, rheumatoid factors, and heterophilic antibodies, are discussed.

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“…14,24 Analogous to the AHA to the upper hinge of Fab molecules, these AHA can act as surrogate Fc or introduce assay artifacts. Thus, development of a F(ab 0 ) 2 format that impedes AHA binding is desirable.…”

Section: Igg1 With the Lower Hinge Of Igg2 Cannot Be Cleaved Efficientlymentioning

confidence: 99%

Evading pre-existing anti-hinge antibody binding by hinge engineering

Kim¹,

Kim²,

Zheng³

et al. 2016

mAbs

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Antigen-binding fragments (Fab) and F(ab 0 ) 2 antibodies serve as alternative formats to full-length antibodies in therapeutic and immune assays. They provide the advantage of small size, short serum half-life, and lack of effector function. Several proteases associated with invasive diseases are known to cleave antibodies in the hinge-region, and this results in anti-hinge antibodies (AHA) toward the neoepitopes. The AHA can act as surrogate Fc and reintroduce the properties of the Fc that are otherwise lacking in antibody fragments. While this response is desired during the natural process of fighting disease, it is commonly unwanted for therapeutic antibody fragments. In our study, we identify a truncation in the lower hinge region of the antibody that maintains efficient proteolytic cleavage by IdeS protease. The resulting neoepitope at the F(ab 0 ) 2 C-terminus does not have detectable binding of pre-existing AHA, providing a practical route to produce F(ab 0 ) 2 in vitro by proteolytic digestion when the binding of preexisting AHA is undesired. We extend our studies to the upper hinge region of the antibody and provide a detailed analysis of the contribution of C-terminal residues of the upper hinge of human IgG1, IgG2 and IgG4 to pre-existing AHA reactivity in human serum. While no pre-existing antibodies are observed toward the Fab of IgG2 and IgG4 isotype, a significant response is observed toward most residues of the upper hinge of human IgG1. We identify a T 225 L variant and the natural C-terminal D 221 as solutions with minimal serum reactivity. Our work now enables the production of Fab and F(ab 0 ) 2 for therapeutic and diagnostic immune assays that have minimal reactivity toward pre-existing AHA.

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Cross-reactive and pre-existing antibodies to therapeutic antibodies—Effects on treatment and immunogenicity

Cited by 94 publications

References 107 publications

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

Pre-existing Antibody: Biotherapeutic Modality-Based Review

Evading pre-existing anti-hinge antibody binding by hinge engineering

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