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Antibody engineering by natural selection and by design

Project description

Antibody engineering for vaccination strategies

Antibodies serve as a defence mechanism that responds to and counteracts a specific antigen. They are developed as drugs for the prevention and therapy of infectious diseases. The production of antibody diversity represents an exceptional example of protein engineering coupled to a strict mechanism of clonal selection. The EU-funded ENGRAB project will explore mechanisms of antibody diversification and engineering with the aim to improve antibodies’ therapeutic impact. It will develop an integrated bioinformatics platform to reveal the clonal dynamics of antibody responses. ENGRAB will formulate and test hypotheses on the factors that drive antibody selection in primary and recall responses, delivering a rational basis for vaccination strategies for HIV, herpes simplex virus, Staphylococcus aureus and Mycobacterium tuberculosis.

Objective

Antibodies represent a powerful defense mechanism due to their capacity to link specific antigen recognition with effector functions and are currently developed as drugs for prophylaxis and therapy of infectious diseases. The generation of antibody diversity represents a remarkable example of protein engineering that is coupled to a stringent mechanism of clonal selection. In the ENGRAB project we propose first to develop an integrated bioinformatics platform to unravel the clonal dynamics of antibody responses and use it to formulate and test hypotheses on the factors that drive antibody selection in primary and recall responses, thus providing a rational basis for vaccination strategies. Second, we will establish the general relevance and impact of receptor-based antibodies, a new type of naturally engineered antibodies generated by templated DNA insertions into immunoglobulin genes. Third, we will use different bispecific antibody formats, including those produced by templated insertions, to engineer, in the same molecule, two binding sites for the HIV spike in order to increase neutralization potency and breadth. Fourth, we will engineer the Fc portion of antibodies to HSV, S. aureus and M. tuberculosis to increase their effector function through loss-of-binding to pathogen Fc receptors or gain-of-binding to human activatory Fc receptors. The program is strongly supported by preliminary findings and will deliver an innovative platform to interrogate natural antibody repertoires and new strategies to engineer antibodies to improve their therapeutic efficacy. The ENGRAB project deals with mechanisms of antibody diversification and engineering with implications for vaccination and immunotherapy. It is therefore submitted to LS6. Given its translational potential it also falls within the scope of LS7.

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Keywords

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Programme(s)

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Topic(s)

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Funding Scheme

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ERC-ADG - Advanced Grant

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Call for proposal

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(opens in new window) ERC-2019-ADG

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Host institution

FONDAZIONE ISTITUTO NAZIONALE DI GENETICA MOLECOLARE INGM
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 2 478 125,00
Address
VIA FRANCESCO SFORZA 35
20122 Milano
Italy

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Region
Nord-Ovest Lombardia Milano
Activity type
Research Organisations
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 2 478 125,00

Beneficiaries (1)

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