The specificity of antibodies to the F(ab′)<sub>2</sub> fragment of human IgG

Heimer, Ralph; Wolfe, Lawrence D.; Abruzzo, John L.

doi:10.1002/art.1780280516

Cited by 11 publications

(5 citation statements)

References 14 publications

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“…Prevalence figures of 98% in study populations consisting of healthy individuals and individuals diagnosed with a disease have been reported 16 . The finding that F(ab′) 2 -autoreactivity is generally more abundant than Fab-autoreactivity is also consistent with previous observations in people 17,18 . Proposed roles for anti-F(ab′) 2 -autoantibodies include clearance of proteolyzed antibodies 19, mitigation of B cell responses in autoimmune disease 20 and restoration of Fc-mediated effector functions in proteolytically inactivated IgG 21 .…”

Section: Discussionsupporting

confidence: 92%

Pre-existing canine anti-IgG antibodies: implications for immunotherapy, immunogenicity testing and immunoassay analysis

Bergman

Bäckström

Hansson-Hamlin

et al. 2020

Sci Rep

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one of the most enigmatic features of humoral immunity is the prevalent presence of circulating autoantibodies against igG. these autoantibodies consist of several subsets, including rheumatoid factors, anti-fab/anti-f(ab′) 2-autoantibodies, and anti-idiotypic antibodies. Anti-igG autoantibodies can impair the safety and efficacy of therapeutic antibodies and interfere with immunogenicity tests in clinical trials. They can also cross-react with allospecific IgG, presenting as heterophilic antibodies that interfere with diagnostic immunoassays. Owing to these factors, recent years have seen a resurgent interest in anti-IgG autoantibodies, but their underlying clinical significance, as well as biological roles and origins, remain opaque. Increased knowledge about canine anti-IgG autoantibodies could facilitate the development of canine immunotherapies and help in understanding and counteracting immunoassay interference. This study investigated the clinical significance and interconnection of heterophilic antibodies, anti-fab, and anti-f(ab′) 2-autoantibodies in dogs. We performed a 2-year prospective follow-up of dogs with heterophilic antibodies and analyzed serum for anti-Fab and anti-f(ab′) 2-autoantibodies. Canine heterophilic antibodies can persist for at least 2 years in serum. A widespread occurrence of anti-Fab and anti-F(ab′) 2-autoantibodies was found, with reactivity to cryptic epitopes in the IgG hinge region and sporadic cross-reactivity with mouse IgG. Canine anti-fab and anti-f(ab′) 2-autoantibodies are thus potential sources of clinical immunogenicity and immunoassay interference. Immunotherapy has revolutionized the treatment of previously incurable diseases. By the end of 2019, 79 therapeutic monoclonal antibodies (mAbs) had been approved by the US Food and Drug Administration (FDA) for the treatment of a variety of human diseases 1, but only a handful of veterinary mAbs are approved, including two for the treatment of cancer in dogs 2. One of several factors holding back this development is a lack of basic information about the canine immune system, including factors influencing the immunogenicity of therapeutic antibodies. Immunogenicity is a significant barrier to the approval of therapeutic mAbs and is only detectable after years of basic research, development and preclinical studies. Thus, accurate prediction of immunogenicity is one of the keys to successful drug development. Because immunological tolerance is highly species-specific, mAbs developed for human patients are immunogenic in animals and not suitable for use in veterinary medicine. Therapeutic mAbs are therefore normally speciated (humanized, caninized or felinized) to reduce their immunogenicity, but despite these efforts, all therapeutic mAbs elicit immune responses in some patients 3. Pre-existing anti-IgG antibodies in treatment-naïve patients are another source of immunogenicity. This umbrella term includes antibodies against autologous IgG, such as rheumatoid factors that bind to the Fc region of IgG. There are also anti-Fab...

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Section: Discussionsupporting

confidence: 92%

Pre-existing canine anti-IgG antibodies: implications for immunotherapy, immunogenicity testing and immunoassay analysis

Bergman

Bäckström

Hansson-Hamlin

et al. 2020

Sci Rep

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“…Early publications report on the existence of single donor-derived abs reacting with the F(ab') 2 -or Fab'-region of plasma pool-derived IgG [5][6][7]. However, the following specified observations are based on the results of more detailed subsequent examinations and belong to the most important experimental findings:…”

Section: Indications Of Fab-fab Interactions During Dimer Formation: mentioning

confidence: 96%

IgG Dimers in Multidonor-Derived Immunoglobulins: Aspects of Generation and Function

Gronski¹

2006

CPD

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Immunoglobulin G (IgG) concentrates for therapeutic purposes, like passive immunotherapy, supplementation in inherited or acquired deficiencies or immunomodulation, are prepared from multidonor-derived plasma pools. They usually contain varying amounts of dimeric IgG. The essential factor influencing dimer formation is the pool size; in addition, molecular properties of IgG and a variety of production process- and formulation-specific parameters are important. Numerous experimental findings suggest that dimers are predominantly generated by interactions of idiotypic and anti-idiotypic antibodies (Ids, anti-Ids). Ab-inherent crossreactivity, frequency distribution of both the affinities for particular Id-anti-Id interactions and the corresponding dimer concentrations still have to be elucidated. All these parameters influencing molecular features and functional activity of IgG dimers hamper the assay-dependent measurement of biological efficacy and correlation of total IgG content. A more detailed understanding may help to better control the dual nature of dimer-dependent biological activity comprising both undesirable (e.g., hypotension) and desirable effects of dimeric IgG (blockade of the reticuloendothelial system, RES, in immune thrombocytopenic purpura, ITP). These effects are detectable in in vitro and in vivo models and are thought to be of relevance for humans.

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“…Anti-hinge NAbs have even earlier been studied and named "pepsin agglutinators," because they agglutinated IgG upon its treatment with pepsin that generates F(ab') 2 and Fc. 22,23 IgG anti-hinge antibodies are germline-encoded NAbs that bind to a conformational hinge region epitope that becomes accessible exclusively upon cleavage of IgG1 by pepsin. 24 Anti-hinge NAbs have an important role in the regulation of the B-cell antibody production.…”

Section: Anti-hinge Nabs Rigidify F(ab') 2 -Ic To Capture Dimeric C3bmentioning

confidence: 99%

How Immune Complexes from Certain IgG NAbs and Any F(ab′)2 Can Mediate Excessive Complement Activation

Lutz

2012

Advances in Experimental Medicine and Biology

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In sepsis death follows an excessive inflammatory response involving cytokines and complement that is activated primarily via the amplifying C3/C5 convertase. Excessive stimulation of complement amplification requires IgG-containing or F(ab')₂-containing immune complexes (IC) that capture dimeric C3b on one of their heavy chains or heavy chain fragments. The ability of IgG-IC to capture dimeric C3b by the Fab portion is dependent on an affinity for C3 within the Fab portion, but outside the antigen-binding region. This property is rare among IgG NAbs. In contrast to this, the lack of the Fc portion renders the Fab regions of any F(ab')(2)-IC accessible to nascent C3b, but dimeric C3b deposits only if F(ab')₂-IC form secondary IC with anti-hinge NAbs that rigidify the complex and thereby promote deposition of dimeric C3b. Both types of complexes, C3b₂-IgG-IC and C3b₂-F(ab')₂-IC/anti-hinge NAbs, are potent precursors of alternative C3 convertases and stimulate complement amplification along with properdin up to 750 times more effectively than C3b and properdin. F(ab')₂ fragments are not normally generated, but are formed from NAbs by enzymes from pathogens and neutrophils in sepsis. Unlike IgG-IC F(ab')₂-IC are not cleared by Fc-receptor dependent processes and circulate long enough to form secondary IC with anti-hinge NAbs that rigidify the complexes such that they capture dimeric C3b and gain the potency to stimulate complement amplification.

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The specificity of antibodies to the F(ab′)₂ fragment of human IgG

Cited by 11 publications

References 14 publications

Pre-existing canine anti-IgG antibodies: implications for immunotherapy, immunogenicity testing and immunoassay analysis

Pre-existing canine anti-IgG antibodies: implications for immunotherapy, immunogenicity testing and immunoassay analysis

IgG Dimers in Multidonor-Derived Immunoglobulins: Aspects of Generation and Function

How Immune Complexes from Certain IgG NAbs and Any F(ab′)2 Can Mediate Excessive Complement Activation

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The specificity of antibodies to the F(ab′)2 fragment of human IgG

Cited by 11 publications

References 14 publications

Pre-existing canine anti-IgG antibodies: implications for immunotherapy, immunogenicity testing and immunoassay analysis

Pre-existing canine anti-IgG antibodies: implications for immunotherapy, immunogenicity testing and immunoassay analysis

IgG Dimers in Multidonor-Derived Immunoglobulins: Aspects of Generation and Function

How Immune Complexes from Certain IgG NAbs and Any F(ab′)2 Can Mediate Excessive Complement Activation

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The specificity of antibodies to the F(ab′)₂ fragment of human IgG