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

Abstract

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.

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

“…By integrating a standardized description of the modes of action and effects of monoclonal antibodies in MG into IMGT/mAb-DB, IMGT ® offers a more complete understanding of how these mAbs function. IMGT ® continues standardized efforts to characterize the mechanisms of action of mAbs targeting various targets in autoimmune diseases, as it was performed with targets in cancer treatment [24], and the goal is to cover the complete IMGT/mAb-DB. living with Myasthenia Gravis, who is committed to dedicating her life to fostering a deeper understanding of this condition.…”

“…Currently, IMGT ® , the international ImMunoGeneTics information system ® (http://www.imgt.org) [23], extends the characterization of therapeutic antibodies with the description of their mechanisms of action and makes them available through its database for mAbs and fusion proteins, IMGT/mAb-DB [24]. In this study, we analyze fifteen mAbs and fusion proteins developed to treat Myasthenia Gravis and autoimmune diseases with auto-antibodies.…”

Monoclonal Antibody based Therapy against Cancer

“…This mechanism involves the mAbs binding to the ligands or receptors on the cell surface, thereby inhibiting the ligand from binding to the cell surface [14]. This may be achieved by conjugated or unconjugated mAbs.…”

A Comprehensive Review of Monoclonal Antibodies in Modern Medicine: Tracing the Evolution of a Revolutionary Therapeutic Approach

“…The Fab region contains complementarity-determining regions (CDRs) that allow the antibody to bind to a specific antigen epitope with high affinity. The heavy chain forms the lower part of the "Y" and is the constant region, while the light chain forms the upper arms and is the variable region responsible for antigen binding [15][16][17][18].…”