Altered antibodies having improved antigen-binding affinity

Details Altered antibodies having improved antigen-binding affinity Altered antibodies having improved antigen-binding affinity

C - Chemistry, Metallurgy

12

N

C12N 15/13 (2006.01) A61K 39/395 (2006.01) C07K 16/28 (2006.01) C12P 21/00 (2006.01)

Patent

CA 2533593

The invention relates to methods of modulating the antigen-binding affinity of an antibody by determining, using data corresponding to the structure of a complex between the antibody and an antigen in a solvent, a representation of a charge distribution of the CDRs of the antibody which minimizes electrostatic contribution to binding free energy between the antibody and the antigen in a solvent. Guided by these determinations, the antibody is accordingly modified (altered) to improve upon, e.g., antibody/antigen binding by modifying at least one amino acid residue to decrease the binding free energy between the antibody and antigen when bound in a solvent.

La présente invention se rapporte à des procédés permettant de moduler l'affinité de liaison à l'antigène d'un anticorps, qui consiste à déterminer, à l'aide de données correspondant à la structure d'un complexe entre l'anticorps et un antigène contenus dans un solvant, une représentation de la distribution de charge des CDR (régions de détermination de la complémentarité) de l'anticorps qui réduise au minimum la contribution électrostatique à l'énergie libre de liaison entre l'anticorps et l'antigène dans un solvant. Sur la base desdites déterminations, l'on modifie l'anticorps de façon à améliorer la liaison anticorps/antigène, par exemple, en modifiant au moins un résidu d'acide aminé afin de réduire l'énergie libre de liaison entre l'anticorps et l'antigène lorsque ces derniers sont liés dans un solvant.

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