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A generic method for design of oligomer-specific antibodies.

ABSTRACT: Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated with oligomer-specific antibodies are not well understood, and this limits targeted design and development. We present here a generic method that enables the design and optimisation of oligomer-specific antibodies. The method takes a two-step approach where discrimination between oligomers and fibrils is first accomplished through identification of cryptic epitopes exclusively buried within the structure of the fibrillar form. The second step discriminates between monomers and oligomers based on differences in avidity. We show here that a simple divalent mode of interaction, as within e.g. the IgG isotype, can increase the binding strength of the antibody up to 1500 times compared to its monovalent counterpart. We expose how the ability to bind oligomers is affected by the monovalent affinity and the turnover rate of the binding and, importantly, also how oligomer specificity is only valid within a specific concentration range. We provide an example of the method by creating and characterising a spectrum of different monoclonal antibodies against both the A? peptide and ?-synuclein that are associated with Alzheimer's and Parkinson's diseases, respectively. The approach is however generic, does not require identification of oligomer-specific architectures, and is, in essence, applicable to all polypeptides that form oligomeric and fibrillar assemblies.

SUBMITTER: Brannstrom K

PROVIDER: S-EPMC3949727 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A generic method for design of oligomer-specific antibodies.

Brännström Kristoffer K Lindhagen-Persson Malin M Gharibyan Anna L AL Iakovleva Irina I Vestling Monika M Sellin Mikael E ME Brännström Thomas T Morozova-Roche Ludmilla L Forsgren Lars L Olofsson Anders A

PloS one 20140311 3

Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated with oligomer-specific antibodies are not well understood, and this limits targeted design and development. We present here a generic method that enables the design and optimisation of oligomer-specif ...[more]

PMID: 24618582

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Project description:OBJECTIVES:The present study aimed to evaluate the iLead intervention and to investigate whether or not transfer of training can be supported by contextualising the intervention (recruiting all managers from one branch of the organisation while focusing on one implementation case, as well as training senior management). DESIGN:A pre-evaluation-postevaluation design was applied using mixed methods with process and effect surveys and interviews to measure the effects on three levels. SETTING:Healthcare managers from Stockholm's regional healthcare organisation were invited to the training. PARTICIPANTS:52 managers participated in the iLead intervention. Group 1 consisted of 21 managers from different organisations and with different implementation cases. Group 2, representing the contextualised group, consisted of 31 managers from the same organisation, working on the same implementation case, where senior management also received training. INTERVENTION:iLead is an intervention where healthcare managers are trained in implementation leadership based on the full-range leadership model. PRIMARY OUTCOME MEASURES:Reactions, knowledge and implementation leadership are measured. RESULTS:Quantitative and qualitative analyses indicate that iLead was perceived to be of high quality and capable of increasing participants' knowledge. Mixed effects were found regarding changes in behaviours. The contextualisation did not have a boosting effect on behaviour change. Hence, group 2 did not increase its active implementation leadership in comparison with group 1. CONCLUSIONS:iLead introduces a new approach to how implementation leadership can be trained when knowledge of effective leadership for implementations is combined with findings on the importance of environmental factors for the transfer of training. Even though managers reported general positive effects, transfer was not facilitated through the contextualisation of the intervention. There is a need to further develop approaches to help participants subsequently apply the learnt skills in their work environment.

Dataset Information

A generic method for design of oligomer-specific antibodies.

Publications

A generic method for design of oligomer-specific antibodies.

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