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

Abstract

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...

Case Report: Anti-GABAA Receptor Encephalitis in a Dog

“…In our case, the titer decreased by four levels. Such a rapid decrease could be explained by a shorter half-life of IgG in dogs compared to humans; in fact, the canine IgG half-life is unknown ( 47 ). A laboratory inaccuracy [inadvertent deviations by 1 titer level are occasionally hard to avoid ( 48 )] may have contributed to the rapid titer decline.…”

Prevalence of heterophilic antibodies in serum samples from horses in an equine hospital, and elimination of interference using chicken IgY

“…Of the 11 positive horses, three were sampled and assayed on multiple occasions and tested positive only once, with less than a month between the different samples. A transient character and low affinity of heterophilic antibodies has been described [29,30], although they have been described to persist for several years in dogs [31]. The reactivity of these samples was rather weak, and a variation between different runs may contribute to the shifting results.…”