Variant immunoglobulins with improved manufacturability

摘要

This invention relates to the modification of the amino acid sequence of an immunoglobulin molecule at certain key positions within regions of the VH and VL FR and CDR3 domains and/or the CH1 domain which are prone to aggregation. Immunoglobulins modified as described may display improved manufacturability, for example, reduced aggregation propensity and/or increased production levels.

主权项

1. A method of improving the manufacturability of an immunoglobulin, wherein the immunoglobulin is a whole antibody or an Fab antibody fragment, the method comprising;
identifying a parent immunoglobulin having a VL domain and a VH domain, introducing one or both of: (i) a substitution at a position selected from the group consisting of 37, 45 and 46 of the VL domain sequence of the parent immunoglobulin, or (ii) a substitution at a position selected from the group consisting of 1, 17, 94, 95, 96, 100, 100d and 102 of the VH domain sequence of the parent immunoglobulin, thereby producing a variant immunoglobulin having a VL domain and a VH domain which displays both reduced aggregation propensity and increased productivity upon expression relative to the parent immunoglobulin, wherein said substitution is introduced by mutation of the nucleic acid encoding the immunoglobulin or by synthesis of a nucleic acid encoding the immunoglobulin with a substitution at said position.