CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common β chain of the IL-3, GM-CSF and IL-5 receptors

Abstract

The β common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of haematopoietic cells via a receptor complex incorporating cytokine-specific α and shared β common (βc, CD131) receptor. Evidence from animal models and recent clinical trials demonstrate that these cytokines are critical mediators of the pathogenesis of inflammatory airway disease such as asthma. However, no therapeutic agents, other than steroids, that specifically and effectively target inflammation mediated by all 3 of these cytokines exist. We employed phage display technology to identify and optimize a novel, human monoclonal antibody (CSL311) that binds to a unique epitope that is specific to the cytokine-binding site of the human βc receptor. The binding epitope of CSL311 on the βc receptor was defined by X-ray crystallography and site-directed mutagenesis. CSL311 has picomolar binding affinity for the human βc receptor, and at therapeutic concentrations is a highly potent antagonist of the combined activities of IL-3, GM-CSF and IL-5 on primary eosinophil survival in vitro. Importantly, CSL311 inhibited the survival of inflammatory cells present in induced sputum from human allergic asthmatic subjects undergoing allergen bronchoprovocation. Due to its high potency and ability to simultaneously suppress the activity of all 3 β common cytokines, CSL311 may provide a new strategy for the treatment of chronic inflammatory diseases where the human βc receptor is central to pathogenesis. The coordinates for the βc/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU).

Modeling TH2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma

“…Thus, this study demonstrated that the βc plays a novel role in regulating allergic disease by regulating multiple effector arms (T H 2 cell, mast cell, dendritic cell, and eosinophil function) and represents a novel anti‐inflammatory target. The therapeutic value of targeting the βc for the treatment of asthma is currently being explored …”

“…The therapeutic value of targeting the βc for the treatment of asthma is currently being explored. 116…”

The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies suggests novel therapeutic opportunities

“…Other mechanisms of antagonism are also likely to be effective, including those that principally inhibit GM-CSF interactions with βc. 45 The F1 and 4D4 antibodies were selected by nature or by experimentation, respectively, on the basis of their ability to inhibit GM-CSF function, but it is interesting to note that at least one other GM-CSF inhibitory molecule occurs in nature and has a completely distinct origin. The GM-CSF/IL-2 inhibition factor (GIF) is expressed by the orf virus, and it has been shown to antagonize both ovine GM-CSF and IL-2, although interestingly not their human orthologues, 46 by binding to these cytokines through mutually exclusive binding sites and is likely to act as a competitive decoy receptor.…”

Avaliação do perfil inflamatório dos pacientes pediátricos com asma grave e sua correlação com o controle da doença e parâmetros funcionais

“…Ele é produzido tanto por células Th1 e Th2 e por uma variedade de células estruturais e inflamatórias, incluindo células do epitélio respiratório, músculo liso, fibroblastos, mastócitos, eosinófilos e macrófagos45 . O GM-CSF, produzido abundantemente pelas células epiteliais pulmonares, promove a diferenciação e proliferação das células hematopoiéticas progenitoras de granulócitos/macrófagos e regula a sobrevida e função de neutrófilos, eosinófilos, macrófagos e células dendríticas50 . Na asma e DPOC a expressão de GM-CSF é elevada no escarro e no lavado broncoalveolar50 .…”

“…O GM-CSF, produzido abundantemente pelas células epiteliais pulmonares, promove a diferenciação e proliferação das células hematopoiéticas progenitoras de granulócitos/macrófagos e regula a sobrevida e função de neutrófilos, eosinófilos, macrófagos e células dendríticas50 . Na asma e DPOC a expressão de GM-CSF é elevada no escarro e no lavado broncoalveolar50 . O GM-CSF regula a imunidade e inflamação da mucosa e função neutrofílica.…”