Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics

Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target ‘foreign’ sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xenosequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics ‘quality by design’, may lead to the development of ever more clinically effective, but less immunogenic, biologics

Du self-control lymphocytaire B aux abords thérapeutiques, quelles voies « B-intrinsèques » pour tempérer les réponses et la mémoire IgE ?

International audiencePersisting adaptive humoral immunity relies on two key cell types: memory B lymphocytes and long-lived plasma cells. Independently from the specific Ig class they produce, those cells can on one side maintain immunity but on the other side account for dysimmune conditions or hypersensitivity. Stringent control is thus required for both their generation and their survival. Among Ig classes, IgE carries the most powerful pro-inflammatory properties, even at minimal concentration. IgE responses and memory, although protecting against parasites and certain venoms, can inversely mediate devastating effects. The long-term memory of anaphylactic responses against allergens thus stands as the black side of IgE responses, accounting for chronic conditions punctuated with dramatic acute adverse events, some eventually lethal. To manage both their value and their danger, the immune system has evolved with multiple and drastic safeguards around IgE responses, notably ensuring a “B-cell self control” which could now be exploited and reinforced by new specific therapeutic strategies.La persistance de l’immunité humorale adaptative repose particulièrement sur 2 acteurs clés : les lymphocytes B mémoires et les plasmocytes à longue durée de vie. Indépendamment de la classe d’immunoglobuline produite, ces cellules peuvent maintenir tant la protection contre des pathogènes que des manifestations d’hypersensibilité ou d’immunopathologie. Elles requièrent donc une régulation stricte de leur génération comme de leur survie. Parmi toutes les classes d’immunoglobuline produites, l’IgE constitue l’anticorps aux propriétés les plus puissantes, pouvant déclencher des réactions inflammatoires majeures même à doses infimes. Les réponses et la mémoire de classe IgE, au rôle protecteur contre les parasites et certains venins ou toxines, sont conservées par l’évolution chez la quasi-totalité des mammifères. Cependant, les réponses anaphylactiques aux venins peuvent à l’inverse être dramatiques et la mémoire à long terme des sensibilisations et des réactions anaphylactiques contre les allergènes constitue le côté obscur des IgE, responsable de pathologies chroniques ponctuées d’évènements aigus parfois fatals. Face à leur utilité mêlée de dangerosité, l’évolution du système immunitaire a entouré les réponses IgE des cellules B de multiples et stricts garde-fous, un self-control naturel en renfort duquel s’ouvrent aujourd’hui de nouvelles voies thérapeutiques

Deletion of the immunoglobulin heavy chain 3' regulatory region super-enhancer affects somatic hypermutation in B1 B cells

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Specific impairment of proximal tubular cell proliferation by a monoclonal κ light chain responsible for Fanconi syndrome.

International audienceBackground Fanconi syndrome (FS) is a rare renal disorder featuring proximal tubule dysfunction that may occur following tubular reabsorption of a monoclonal light chain (LC), in patients with multiple myeloma. FS may precede the recognition of multiple myeloma by several years. In most cases, crystalline inclusions of monoclonal κ LCs are observed within the lysosomes of proximal tubular cells (PTCs) and probably participate in their functional alteration. Methods To investigate the mechanism implicated in proximal tubule dysfunction, we compared the effects of κ LC-CHEB obtained from a patient with myeloma-associated FS to those of control κ LC-BON obtained from a patient without evidence of FS, on the viability and proliferation of two different PTC lines. Results Our data suggest that the tubular atrophy in myeloma-associated FS does not result from increased apoptosis of PTCs, but from their impaired capacity to proliferate and renew. Indeed, in vitro incubation of cultured PTCs with physiological amounts of the nephrotoxic κ LC-CHEB was sufficient to cause a depression in DNA synthesis and in cell proliferation. This effect was observed neither with control κ LC-BON nor in the absence of κ LC. Conclusions The reduced turnover of PTCs may affect tubular repair and regeneration. In addition, the reduced proliferation of myeloma cells producing the same monoclonal κ LC might explain the frequent association of FS with smoldering multiple myeloma