Critical Parameters for the Development of Novel Therapies for Severe and Resistant Infections-A Case Study on CAL02, a Non-Traditional Broad-Spectrum Anti-Virulence Drug.

Background: Poor outcomes in severe and resistant infections, together with the economic struggles of companies active in the field of anti-infective development, call for new solutions and front runners with novel approaches. Among "non-traditional" approaches, blocking virulence could be a game changer.

Objectives: This review offers a perspective on parameters that have determined the development path of CAL02, a novel anti-virulence agent, with a view to steering clear of the obstacles and limitations that impede market sustainability for new anti-infective drugs.

CAL02, a novel antitoxin liposomal agent, in severe pneumococcal pneumonia: a first-in-human, double-blind, placebo-controlled, randomised trial.

Background: Severe community-acquired pneumonia caused by Streptococcus pneumoniae is associated with high morbidity and mortality rates. CAL02, a novel antitoxin agent with an unprecedented mode of action, consists of liposomes that capture bacterial toxins known to dysregulate inflammation, cause organ damage, and impede immune defence. We aimed to assess the safety of CAL02 as an add-on therapy to antibiotics.

Liposomes as novel anti-infectives targeting bacterial virulence factors?

A recent report commissioned by Prime Minister David Cameron and chaired by former Goldman Sachs chief economist Jim O'Neill warns that the emergence, persistence and spread of antimicrobial resistance could lead to 10 million deaths per year and cause an economic burden as much as US$100 trillion by 2050. In the midst of this global crisis, unprecedented paths are being explored to combat bacterial infection. Virulence factors, and more particularly pore-forming toxins, play a key role in increasing morbidity and mortality caused by drug-resistant bacterial infections.

Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson's disease.

Phosphorylation is involved in numerous neurodegenerative diseases. In particular, alpha-synuclein is extensively phosphorylated in aggregates in patients suffering from synucleinopathies. However, the share of this modification in the events that lead to the conversion of alpha-synuclein to aggregated toxic species needed to be clarified.

Differential contribution of three activating IgG Fc receptors (FcgammaRI, FcgammaRIII, and FcgammaRIV) to IgG2a- and IgG2b-induced autoimmune hemolytic anemia in mice.

Murine phagocytes express three different activating IgG FcgammaR: FcgammaRI is specific for IgG2a; FcgammaRIII for IgG1, IgG2a, and IgG2b; and FcgammaRIV for IgG2a and IgG2b. Although the role of FcgammaRIII in IgG1 and IgG2a anti-RBC-induced autoimmune hemolytic anemia (AIHA) is well documented, the contribution of FcgammaRI and FcgammaRIV to the development of IgG2a- and IgG2b-induced anemia has not yet been defined. In the present study, using mice deficient in FcgammaRI, FcgammaRIII, and C3, in combination with an FcgammaRIV-blocking mAb, we assessed the respective roles of these three FcgammaR in the development of mild and severe AIHA induced by two different doses (50 and 200 microg) of the IgG2a and IgG2b subclasses of the 34-3C anti-RBC monoclonal autoantibody.

Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies.

The pathogenesis of autoantibody-mediated cellular and tissue lesions in autoimmune diseases is most straightforwardly attributable to the combined action of self-antigen binding properties and effector functions associated with the Fc regions of the different immunoglobulin (Ig) isotypes. The analysis of two different sets of monoclonal autoantibodies derived from lupus-prone mice revealed remarkable differences in the pathogenic potentials of different IgG subclasses: (1) the IgG2a and IgG2b subclasses of anti-red blood cell (RBC) autoantibodies are the most pathogenic and efficiently activate two classes of activating IgG Fc receptors (FcgammaRIII and FcgammaRIV) and complement; (2) the IgG3 subclass is less pathogenic and activate only complement; and (3) the IgG1 subclass is the least pathogenic and interact only with FcgammaRIII. In addition, because of the unique property of IgG3 to form self-associating complexes and generate cryoglobulins, this subclass of rheumatoid factor and anti-DNA autoantibodies became highly pathogenic and induced lupus-like nephritis and/or vasculitis.

Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody.

By generating four IgG isotype-switch variants of the high affinity 34-3C anti-erythrocyte autoantibody, and comparing them to the IgG variants of the low affinity 4C8 anti-erythrocyte autoantibody that we have previously studied, we evaluated in this study how high affinity binding to erythrocytes influences the pathogenicity of each IgG isotype in relation to the respective contributions of Fcgamma receptor (FcgammaR) and complement. The 34-3C autoantibody opsonizing extensively circulating erythrocytes efficiently activated complement in vivo (IgG2a = IgG2b > IgG3), except for the IgG1 isotype, while the 4C8 IgG autoantibody failed to activate complement. The pathogenicity of the 34-3C autoantibody of IgG2b and IgG3 isotypes was dramatically higher (>200-fold) than that of the corresponding isotypes of the 4C8 antibody.

Selective increase of autoimmune epitope expression on aged erythrocytes in mice: implications in anti-erythrocyte autoimmune responses.

We investigated the impact of changes occurring during red blood cell (RBC) ageing on the RBC-binding activity of pathogenic anti-erythrocyte monoclonal antibodies derived from autoimmune-prone New Zealand black (NZB) mice. As assessed by flow cytometric analysis on in vivo biotinylated RBCs, all five NZB-derived anti-RBC mAb exhibited more efficient binding to aged RBCs than to young RBCs, and resulted in a selective elimination of more aged RBCs from the circulating blood. In addition, treatment of RBCs with proteases markedly enhanced the binding of all five anti-RBC mAb, raising the possibility that increased exposure of autoimmune epitopes on aged RBCs may be in part, a result of contacts with proteolytic enzymes during the lifetime of circulating RBCs.