Binding of Immunoglobulin G to Protoporphyrin IX and Its Derivatives: Evidence the Fab Domain Recognizes the Protoporphyrin Ring

Orino, Koichi

doi:10.3390/antib8010006

Cited by 2 publications

(1 citation statement)

References 17 publications

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“…Thus, pioneering works with human and mouse myeloma-derived monoclonal Abs revealed unexpected high frequencies of molecules that interact with nitoarene compounds, especially 2,4-dinitrophenyl 1, 2, 3 . Further studies showed that the human Abs can also recognize other aromatic and heterocyclic molecules, including cofactors or prosthetic groups exploited by enzymes, namely - riboflavin, FAD, ATP, cobalamin, protoporphyrin IX and heme 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 . Human Abs also recognize a xenogenic disaccharide molecule i.e.…”

Section: Introductionmentioning

confidence: 99%

Interaction of clinical-stage antibodies with heme predicts their physiochemical and binding qualities

Lecerf

Kanyavuz

Rossini

et al. 2020

Preprint

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Development of monoclonal antibody therapeutics is a sophisticated process. Early stage detection of negative traits of antibodies, which can impact the production, storage stability or therapeutic efficacy is of critical importance for saving time and resources in drug development programs. Since the developability issues of antibodies are diverse, including expression yield, chemical and physical stability, propensity for aggregation, antigen-binding polyreactivity, etc., a battery of experimental and in silico assays have been developed for thorough examination of drug candidates. Here, by using a set of 113 samples with variable region sequences matching clinical-stage therapeutic antibodies, we demonstrated that unique physicochemical properties of heme allow this cofactor molecule to be applied as a probe for simultaneous detection of different deleterious characteristics of antibodies i.e., antigen-binding polyreactivity, self-association, aggregation, hydrophobicity and expression yield. Moreover, our study demonstrates that similarly as antibody repertoires from healthy individuals, a fraction of therapeutic antibodies acquires use heme as cofactor for recognition of diverse antigens. These results reveal presence of a hidden vulnerability issue for some antibodies, which would not be detectable by standard analytical assays. This liability may be of concern for monoclonal antibodies intended to be use in patients with pathophysiological conditions where extracellular heme is present e.g. hemolysis or tissue damage. We provided evidence about the mechanistic basis of the unique features of heme and offer a powerful analytical tool for rapid and simple detection of important negative traits in candidate therapeutic antibodies.

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Section: Introductionmentioning

confidence: 99%

Interaction of clinical-stage antibodies with heme predicts their physiochemical and binding qualities

Lecerf

Kanyavuz

Rossini

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

Interaction of clinical-stage antibodies with heme predicts their physiochemical and binding qualities

et al. 2021

View full text Add to dashboard Cite

Immunoglobulin repertoires contain a fraction of antibodies that recognize low molecular weight compounds, including some enzymes’ cofactors, such as heme. Here, by using a set of 113 samples with variable region sequences matching clinical-stage antibodies, we demonstrated that a considerable number of these antibodies interact with heme. Antibodies that interact with heme possess specific sequence traits of their antigen-binding regions. Moreover they manifest particular physicochemical and functional qualities i.e. increased hydrophobicity, higher propensity of self-binding, higher intrinsic polyreactivity and reduced expression yields. Thus, interaction with heme is a strong predictor of different molecular and functional qualities of antibodies. Notably, these qualities are of high importance for therapeutic antibodies, as their presence was associated with failure of drug candidates to reach clinic. Our study reveled an important facet of information about relationship sequence-function in antibodies. It also offers a convenient tool for detection of liabilities of therapeutic antibodies.

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Binding of Immunoglobulin G to Protoporphyrin IX and Its Derivatives: Evidence the Fab Domain Recognizes the Protoporphyrin Ring

Cited by 2 publications

References 17 publications

Interaction of clinical-stage antibodies with heme predicts their physiochemical and binding qualities

Interaction of clinical-stage antibodies with heme predicts their physiochemical and binding qualities

Interaction of clinical-stage antibodies with heme predicts their physiochemical and binding qualities

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