Fibronectin binding domains with reduced immunogenicity

摘要

Fibronectin type III (10Fn3) binding domains having novel designs that are associated with reduced immunogenicity are provided. The application describes alternative 10Fn3 binding domains in which certain immunogenic regions are not modified when producing a binder in order to maintain recognition as a self antigen by the host organism. The application also describes 10Fn3 binding domains in which HLA anchor regions have been destroyed thereby reducing the immunogenic contribution of the adjoining region. Also provided are 10Fn3 domains having novel combinations of modified regions that can bind to a desired target with high affinity.

主权项

1. A polypeptide comprising a modified human 10Fn3 domain, which comprises AB, BC, CD, DE, EF and FG loops and β-strands A, B, C, D, E, F and G, wherein the modified 10Fn3 domain comprises modifications only in:
(i) the amino acid sequence of the BC loop relative to the BC loop of the wild-type human 10Fn3 domain (SEQ ID NO: 1); (ii) the amino acid sequence of the FG loop relative to the wild-type human 10Fn3 domain (SEQ ID NO: 1), and (iii) the amino acid sequence of a β-strand selected from the group consisting of β-strand B, β-strand C, and both β-strand B and β-strand C, relative to the β-strand B and the β-strand C of the wild-type human 10Fn3 domain (SEQ ID NO: 1),wherein the modifications in the BC and FG loops contribute to binding the same target, and the modified 10Fn3 domain has reduced immunogenicity relative to a modified 10Fn3 domain comprising the β-strand B and β-strand C of the wild-type human 10Fn3 domain (SEQ ID NO: 1).