Structural & functional characterisation of antibody therapeutics PDF
Preview Structural & functional characterisation of antibody therapeutics
Structural & functional characterisation of antibody therapeutics Digitalis Digitalis Roy Jefferis School of Immunity & Infection, University of Birmingham UK CASSS – Practical Applications of Mass Spectrometry. Marina del Rey, September 2010 Market size: $22 billion in 2007 Projected for 2010: $30 billion 28 licensed; ~ 500 in development 80 in clinical trials; 200 companies Challenge: To reduce: “Cost of Goods” (CoG) “Cost of Treatment” (CoT) Natural & recombinant antibodies protect due to: Neutralisation/blocking of infectious agents and their products: e.g. virus, toxins, venoms cytokines, e.g. TNFα Infliximab, Adalimumab, Golimumab, Cimzia(Fab-Peg) Formation of immune complexes and activation of killing mechanisms e.g. bacteria cancer cells Rituximab, Herceptin, Cetuximab Agonist or antagonist activity (autoimmunity!) Panitumumab, Cetuximab Structural & functional characterisation of antibody therapeutics Antibody classes, isotypes and allotypes Antibody effector activities IgG-Fc glycoforms IgG-Fab glycoforms Biosimilars & Antibody-drug conjugates Human immunoglobulin classes & subclasses The result of gene duplication, mutation and selection IgM IgG IgD IgE IgA IgG1, IgG2, IgG3, IgG4; IgA1, IgA2 The humoral immune response is “orchestrated” to provide optimal protection to a given “insult” Four chain structure of the antibody molecule Hinge region, susceptible to enzymatic cleavage V C L L V C 1 C 2 C 3 H H H H Fab: antigen binding Fc: effector activation Oligosaccharide Interchain disulphide bridges Domain structure of IgG Antigen Antigen binding binding Fab Fab oligosaccharide Fc Effector functions Ludger IIggGG22 IIggGG11 ~ 25 % ~ 60 % SpA/SpG binding SpA/SpG binding IIggGG44 IIggGG33 ~ 5 % ~ 10 % SpA/SpG binding SpG binding IgG subclass of licensed antibody therapeutics Rituxan IgG1κ Golimumab IgG1κ Zenopax IgG1κ Xolair IgG1κ Herceptin IgG1κ Raptiva IgG1κ Remicade IgG1κ Erbitux IgG1κ Simulect IgG1κ Avastin IgG1κ Synagis IgG1κ Mylotarg IgG4κ Campath IgG1κ Tysabri IgG4κ Humira IgG1κ Mylotarg IgG4κ Tocilizumab IgG1κ Vectibix IgG2κ Biacore binding signals (RU) & dissociation constants (Kdiss) for anti-IgG-Fc: R10Z8E9 with human & non-human primate sera Sample (serum) RU KDiss (M) Human 1274 1.77 ×10−10 Cynomolgus 3 No binding Baboon 0 No binding Marmoset 5 No binding Rhesus macaque −3 No binding Chimpanzee 1077 2.21 ×10−10 Stubenrauch K, et al., J Pharm Biomed Anal. 49:1003-1008 (2009)
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