IMGT® Nomenclature of Engineered IGHG Variants Involved in Antibody Effector Properties and Formats

Lefranc, Marie Paule; Lefranc, Gérard

doi:10.3390/antib11040065

Cited by 5 publications

(3 citation statements)

References 136 publications

(198 reference statements)

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“…Mass spectrometry detection of G3m and IGHG3 alleles has been performed for the follow-up of differential mother and neonate IgG3 [168], and molecular validation of the proteomic results has been performed by sequencing [169]. The use of the IMGT unique numbering for C domain in the study of allotypes and the recent motif description of engineered variants modifying the effector and structural properties of the therapeutical antibodies [170] contribute to bridging genes, sequences, structures, and functions despite their diversity and heterogeneity. a In Negroid populations, the G1m17,1 allele frequently includes G1m27 and/or G1m28, leading to three additional G1m.…”

Section: Discussionmentioning

confidence: 99%

Human Gm, Km, and Am Allotypes: WHO/IMGT Nomenclature and IMGT Unique Numbering for Immunoinformatics and Therapeutical Antibodies

Lefranc

2023

BioMedInformatics

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Human immunoglobulin allotypes are allelic antigenic determinants (or “markers”) determined serologically, classically by hemagglutination inhibition, on the human immunoglobulin (IG) or antibody heavy and light chains. The allotypes have been identified on the gamma1, gamma2, gamma3, and alpha2 heavy chains (designated as G1m, G2m, G3m, and A2m allotypes, respectively) and on the kappa light chain (Km allotypes). Gm and Am allotypes have been one of the most powerful tools in population genetics, as they are inherited in fixed combinations, or Gm–Am haplotypes, owing to the linkage of the human IGHC genes in the IGH locus on chromosome 14. They have been very instrumental in molecular characterization of the human IGHC genes (gene polymorphisms or alleles, and IG heavy-chain structure in domains) and of the IGH locus (IGHC gene order, gene conversion, and copy number variation (CNV)). They represent a major system for understanding immunogenicity of the polymorphic IG chains in relation to amino acid and conformational changes. The WHO/IMGT allotype nomenclature and the IMGT unique numbering for constant (C) domain bridge Gm–Am and Km alleles to IGHC and IGKC gene alleles and structures and, by definition, to IG chain immunogenicity, opening the way for immunoinformatics of personalized therapeutic antibodies and engineered variants.

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Section: Discussionmentioning

confidence: 99%

Human Gm, Km, and Am Allotypes: WHO/IMGT Nomenclature and IMGT Unique Numbering for Immunoinformatics and Therapeutical Antibodies

Lefranc

2023

BioMedInformatics

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“…Keywords to best describe the mechanism and the anticipated immune response are included along with the HGNC gene name for the target and its abbreviation. The AA sequences of each mAb were carefully examined using the IMGT/2Dstructure-DB and the IMGT/DomainGapAlign tool [ 25 ] for mutation identifications in the Fc region, and their effects were included in the standardized description, according to IMGT-engineered variants [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

Delving into Molecular Pathways: Analyzing the Mechanisms of Action of Monoclonal Antibodies Integrated in IMGT/mAb-DB for Myasthenia Gravis

Golfinopoulou,

Giudicelli,

Manso

et al. 2023

Vaccines

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Background: Myasthenia Gravis (MG) is a rare autoimmune disease presenting with auto-antibodies that affect the neuromuscular junction. In addition to symptomatic treatment options, novel therapeutics include monoclonal antibodies (mAbs). IMGT®, the international ImMunoGeneTics information system®, extends the characterization of therapeutic antibodies with a systematic description of their mechanisms of action (MOA) and makes them available through its database for mAbs and fusion proteins, IMGT/mAb-DB. Methods: Using available literature data combined with amino acid sequence analyses from mAbs managed in IMGT/2Dstructure-DB, the IMGT® protein database, biocuration allowed us to define in a standardized way descriptions of MOAs of mAbs that target molecules towards MG treatment. Results: New therapeutic targets include FcRn and molecules such as CD38, CD40, CD19, MS4A1, and interleukin-6 receptor. A standardized graphical representation of the MOAs of selected mAbs was created and integrated within IMGT/mAb-DB. The main mechanisms involved in these mAbs are either blocking or neutralizing. Therapies directed to B cell depletion and plasma cells have a blocking MOA with an immunosuppressant effect along with Fc-effector function (MS4A1, CD38) or FcγRIIb engager effect (CD19). Monoclonal antibodies targeting the complement also have a blocking MOA with a complement inhibitor effect, and treatments targeting T cells have a blocking MOA with an immunosuppressant effect (CD40) and Fc-effector function (IL6R). On the other hand, FcRn antagonists present a neutralizing MOA with an FcRn inhibitor effect. Conclusion: The MOA of each new mAb needs to be considered in association with the immunopathogenesis of each of the subtypes of MG in order to integrate the new mAbs as a viable and safe option in the therapy decision process. In IMGT/mAb-DB, mAbs for MG are characterized by their sequence, domains, and chains, and their MOA is described.

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“…Botensilimab (mAbID 1123), an anti-CTLA4 antibody with enhanced Fc-effector function, has been engineered to improve FcgRIIIa affinity while decreasing FcgRIIb binding and boosting effector functions such as ADCC (21). Table S1 and IMGT Biotechnology page (https://www.imgt.org/ IMGTbiotechnology/ > Antibody glycosylation and effector properties > IMGT engineered variant nomenclature: IGHG variants) describe in detail and in a standardized format all engineered antibodies Fc variants (22) provided in this study.…”

Section: Monoclonal Antibodies Targeting Ctla4mentioning

confidence: 99%

Mechanisms of action of monoclonal antibodies in oncology integrated in IMGT/mAb-DB

et al. 2023

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BackgroundCancer cells activate different immune checkpoint (IC) pathways in order to evade immunosurveillance. Immunotherapies involving ICs either block or stimulate these pathways and enhance the efficiency of the immune system to recognize and attack cancer cells. In this way, the development of monoclonal antibodies (mAbs) targeting ICs has significant success in cancer treatment. Recently, a systematic description of the mechanisms of action (MOA) of the mAbs has been introduced in IMGT/mAb-DB, the IMGT® database dedicated to mAbs for therapeutic applications. The characterization of these antibodies provides a comprehensive understanding of how mAbs work in cancer.MethodsIn depth biocuration taking advantage of the abundant literature data as well as amino acid sequence analyses from mAbs managed in IMGT/2Dstructure-DB, the IMGT® protein database, allowed to define a standardized and consistent description of the MOA of mAbs targeting immune checkpoints in cancer therapy.ResultsA fine description and a standardized graphical representation of the MOA of selected mAbs are integrated within IMGT/mAb-DB highlighting two main mechanisms in cancer immunotherapy, either Blocking or Agonist. In both cases, the mAbs enhance cytotoxic T lymphocyte (CTL)-mediated anti-tumor immune response (Immunostimulant effect) against tumor cells. On the one hand, mAbs targeting co-inhibitory receptors may have a functional Fc region to increase anti-tumor activity by effector properties that deplete Treg cells (Fc-effector function effect) or may have limited FcγR binding to prevent Teff cells depletion and reduce adverse events. On the other hand, agonist mAbs targeting co-stimulatory receptors may bind to FcγRs, resulting in antibody crosslinking (FcγR crosslinking effect) and substantial agonism.ConclusionIn IMGT/mAb-DB, mAbs for cancer therapy are characterized by their chains, domains and sequence and by several therapeutic metadata, including their MOA. MOAs were recently included as a search criterion to query the database. IMGT® is continuing standardized work to describe the MOA of mAbs targeting additional immune checkpoints and novel molecules in cancer therapy, as well as expanding this study to other clinical domains.

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IMGT® Nomenclature of Engineered IGHG Variants Involved in Antibody Effector Properties and Formats

Cited by 5 publications

References 136 publications

Human Gm, Km, and Am Allotypes: WHO/IMGT Nomenclature and IMGT Unique Numbering for Immunoinformatics and Therapeutical Antibodies

Human Gm, Km, and Am Allotypes: WHO/IMGT Nomenclature and IMGT Unique Numbering for Immunoinformatics and Therapeutical Antibodies

Delving into Molecular Pathways: Analyzing the Mechanisms of Action of Monoclonal Antibodies Integrated in IMGT/mAb-DB for Myasthenia Gravis

Mechanisms of action of monoclonal antibodies in oncology integrated in IMGT/mAb-DB

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