Therapeutic antibodies: French research organises itself

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Therapeutic antibodies and infectious diseases

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Neonatal Fc receptor, key control of immunoglobulins biodistribution

National audienceNeonatal Fc receptor, key control of immunoglobulins biodistribution In 1969, Brambell, while studying the long serum half-life of IgG and their ability to cross the materno-foetal barrier, attributed these two properties to the existence of a specific Fc receptor, which was later denominated FcRn for neonatal Fc receptor. The resolution of its structure revealed that it is a MHC class-l-like molecule. FcRn is able to load IgG and albumin in a pH-dependent manner. It acts as an intracellular transport protein and as such is controling the serum half-life of these proteins (apical recycling of IgG and albumin in endothelial cells), IgG biodistribution (apical to basolateral and basolateral to apical transport of IgG in epithelial and endothelial cells) and it may also contribute to phagocytosis. FcRn is thus a key partner in the pharmacokinetics of therapeutic antibodies, opening interesting prospects for optimisation of their use

Porcine CD58: cDNA cloning and molecular dissection of the porcine CD58–human CD2 interface

International audience10 The porcine ligands of human CD2 remain unknown in xenotransplantation despite being an important pathway of T cell 11 costimulation. Of the two main candidates, i.e., CD48 and CD58, the cDNA of the most likely ligand poCD58 was cloned from 12 CD48-negative endothelial cells costimulating human CD4 þ T cells through the CD2 pathway. The deduced protein sequence is 244 13 residues long and is 43% homologous to the human sequence. Based on similarity between porcine and human CD58 external V-set 14 Ig-type domains, a structural model of poCD58-huCD2 interaction was built. Most of the charged residues located at the interface 15 with huCD2 are highly conserved. Six putative hydrogen bonds between poCD58 and huCD2 were identified; five involve the same 16 residues as in the syngeneic combination while the sixth is formed between an additional tyrosine in poCD58 and Arg48 in huCD2, 17 increasing the complementarity between the two molecules. These structural data will help us to develop poCD58 blocking agents 18 for xenotransplantation. 19 21 When pig to human xenotransplantation was con-22 sidered in the early 1990s, the problem of hyperacute 23 rejection was first investigated and recently solved by 24 using organs from pig transgenic for complement regu-25 latory proteins [3]. Cellular rejection phenomena were 26 initially underestimated, mainly because previous mur-27 ine/human xenogeneic experiments suggested that phy-28 logenetic divergence prevented the recognition of ligand/ 29 receptor and receptor/counter-receptor pairs in xenoge-30 neic systems. In particular, human T cell responses to 31 xenogeneic (murine) antigen presenting cells (APCs) 32 were considered low due to inability of costimulatory 33 receptors (CD28, CD2, and LFA-1) to be engaged by 34 the costimulatory molecules on murine APC. However, 35 phylogenetic divergence between pig and human is less 36 than between murine and human. Indeed, strong xeno-37 geneic T cell responses to pig APC were observed and 38 costimulation blocking experiments clearly demon-39 strated that human CD28 [5], CD2, and LFA-1 [9] could 40 be engaged by the putative porcine counter-receptors. 41 Characterization of porcine costimulatory molecules 42 was therefore initiated with the description of poCD86 43 (also known as B7-2) [7] and then poCD80 [19]. Sub-44 sequently, molecular, functional, and structural char-45 acterization of porcine CTLA4, one of the poCD86 46 ligands, led to the unexpected finding that this molecule 47 bound weakly to human CD86 and CD80 [18] and failed 48 to inhibit human T cell responses, when used as a 49 CTLA4-Ig fusion protein. Porcine ICAM-1 was recently 50 characterized [14] and demonstrated a low degree of 51 conservation with human ICAM-1 (41% identity at the 52 protein level). However, despite being divergent, porcine 53 ICAM-1 has kept the ability to bind human LFA-1 and 54 to transmit costimulatory signals to human T cells [9]. 55 Up to now, in xenogeneic pig-to-primate models, por-56 cine cells have demonstrated their capacity t

Targets for MAbs: innovative approaches for their discovery & validation, LabEx MAbImprove 6 th antibody industrial symposium, June 25-26, 2018, Montpellier, France

International audienceMonoclonal antibodies (mAbs) have revolutionized the treatment landscape in many disciplines of human medicine. To continue this exciting trend, sustained identification of new, validated and preferably functional targets are needed. However, this is the precise bottleneck in today's development of the next generation of therapeutic mAbs. Failures in translating a target into a successful therapeutic mAb are much more frequent than successes. Labex MAbImprove is a French-led consortium of academic laboratories jointly working on several aspects of the development of next-generation mAbs. The network organizes annual international meetings gathering academia and industry to discuss the different challenges faced in the therapeutic mAbs field. The 2018 symposium (also called AIS2018 and co-organized with MabDesign, the immunotherapy French industrial sector) focused on the discovery and validation of new targets for therapeutic mAbs. Key players from industry and academia outlined a number of exciting contributions, notably dealing with new innovations in the target discovery area, but also lessons learned from failures in the past. This report summarizes the talks presented at the AIS2018. We aim at broad dissemination of the most relevant, unpublished findings presented during the meeting, and hope to inspire all the contributors in this field to take new directions and bring about improvements

Rituximab-related late-onset neutropenia in a patient with severe rheumatoid arthritis

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Insights into the IgG heavy chain engineering patent landscape as applied to IgG4 antibody development

International audienceDespite being the least abundant immunoglobulin G in human plasma, IgG4 are used therapeutically when weak effector functions are needed. The increase in engineered IgG4-based antibodies on the market led us to study the patent landscape of IgG4 Fc engineering, i.e., patents claiming modifications in the heavy chain. Thirty-seven relevant patent families were identified, comprising hundreds of IgG4 Fc variants focusing on removal of residual effector functions (since IgG4s bind to FcγRI and weakly to other FcγRs), half-life enhancement and IgG4 stability. Given the number of expired or soon to expire major patents in those 3 areas, companies developing blocking antibodies now have, or will in the near future, access to free tools to design silenced, half-life extended and stable IgG4 antibodies

Monoclonals Antibodies: a Recent and Major Therapeutic Advance.

International audienceMonoclonals Antibodies: a Recent and Major Therapeutic Advance. Starting in the eighties, therapeutic monoclonal antibodies have profoundly modified the treatment of a number of diseases, such as cancer and chronic inflammatory diseases. The first monoclonal antibodies were of murine origin and had several drawbacks, notably low efficacy and immunogenicity. However, they initiated a breakthrough in therapeutics. Thanks to the development of biotechnology, the human part of the antibody was indeed progressively increased, leading to chimeric, humanized and, finally, fully human monoclonal antibodies. Even if the development of monoclonal antibodies is a complex process, and if some of them may trigger worrying adverse effects, their contribution to therapeutics is major. At present, about twenty monoclonal antibodies are on the market, and a large number is under development

Implications of receptors for the Fc portion of IgG (Fc gamma Rs) in mechanism of action of therapeutic antibodies

National audienceFrom several years ago, recombinant monoclonal antibodies have allowed a revolution in therapeutic approach of cancer patients. Whereas the clinical efficacy of many antibodies is now demonstrated, their mechanism of action in patients remains elusive. For antibodies targeting membrane antigens, they particularly resort to cytotoxic effectors, which expressed receptors for Fc portion of IgG (Fc gamma Rs). This review analyses different functions depending of Fc gamma R and their potential role in mechanism of action of therapeutic antibodies. A better knowledge of these functions should allow in the next future the optimisation of these treatments. triangl