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Development of Dual-targeting Monoclonal Antibodies Against CX3CL1/CX3CR1 and CCL2/CCR2 Axes

Power, Christine A.
Defense Thèse de doctorat : Univ. Genève, 2013 - Sc. 4579 - 2013/06/28
Abstract In murine model of atherosclerosis, co-blockade of CX3CL1 (or CX3CR1) and CCL2 (or CCR2) have shown significant reduction of clinical scores relative to single knockouts suggesting that successful therapeutic intervention may require blockade of more than one chemokine axis. In this thesis, three proof-of-concept strategies were designed to generate dual-targeting monoclonal antibodies (MAbs) for the inhibition of CX3CL1/CX3CR1 and CCL2/CCR2 interactions. In one approach, an immunocytokine made from the direct N-terminal fusion of an antagonist of CCR2 (7ND-CCL2) to the light chain or the heavy chain of a neutralising MAb against CX3CL1 was shown to inhibit CX3CL1 and CCL2 induced cell chemotaxis. In another approach using phage display a partial neutralising antibody against CX3CL1 and CCL2 was identified. The third strategy was an attempt to make an antibody-drug conjugate using a small molecule antagonist of CCR2 bound to an anti-CX3CL1 neutralising MAb, in a site-specific manner via a Selenocysteine residue.
Keywords Antibody engineeringCX3CL1CCL2dual-targeting antibodies
URN: urn:nbn:ch:unige-290125
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Research group Merck Serono S.A Genève
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MUSOLINO, Najia. Development of Dual-targeting Monoclonal Antibodies Against CX3CL1/CX3CR1 and CCL2/CCR2 Axes. Université de Genève. Thèse, 2013. https://archive-ouverte.unige.ch/unige:29012

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Deposited on : 2013-07-31

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