IL4/IL13 binding repeat proteins and uses
IL4/IL13-binding proteins comprise binding domains, which inhibit IL4/IL13 binding to IL4Ralpaha and common gamma chain complexes (Type 1) and inhibit IL4 binding to IL4Ralpha and IL13Ralpha1 complexes (Type 2), and IL13 binding to IL13Ralpha1 and/or IL13Ralpha2, are useful in the treatment of cancer, inflammatory, and other pathological conditions, such as allergic or fibrotic conditions, especially pulmonary conditions.
1. A binding protein comprising a binding domain, an amino terminal cap (N-cap) module and a carboxy terminal cap (C-cap) module, wherein the binding protein binds to human IL4 and inhibits human IL4 binding to IL4Ralpha in vitro or in vivo, and the binding domain is an ankyrin repeat domain and comprises an ankyrin repeat (AR1) module positioned C-terminal to the N-cap comprising the amino acid sequence of SEQ ID NOS: 39 or 88, an ankyrin repeat (AR2) module positioned C-terminal to the AR1 module comprising the amino acid sequence of SEQ ID NOS: 89 or 180, and an ankyrin repeat (AR3) module positioned C-terminal to the AR2 module comprising the amino acid sequence of SEQ ID NO: 181 and wherein the N-cap module is positioned N-terminal to the ankyrin repeat domain comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 171, and 174 and the C-cap module is positioned C-terminal to the ankyrin repeat domain comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 3, 103, 172, and 175.
2. An IL4 binding protein comprising the amino acid sequence of SEQ ID NO: 184.
3. An IL13 binding protein comprising the amino acid sequence of SEQ ID NO: 185.
4. A binding protein comprising a binding domain, an amino terminal cap (N-cap) module and a carboxy terminal cap (C-cap) module, wherein the binding domain is an ankyrin repeat domain and binds to human IL13 in vitro or in vivo, inhibiting human IL13 binding to at least one of human IL13Ralpha1 and human IL13Ralpha2, and wherein the binding protein comprises an ankyrin repeat (AR1) module positioned C-terminal to the N-cap comprising the amino acid sequence of SEQ ID NOS: 108 or 109, an ankyrin repeat (AR2) module positioned C-terminal to the AR1 module comprising the amino acid sequence of SEQ ID NOS: 126, 158, 159, or 182, and an ankyrin repeat (AR3) module positioned C-terminal to the AR2 module comprising the amino acid sequence of SEQ ID NO: 183 and wherein the N-cap module is positioned N-terminal to the ankyrin repeat domain comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 171, and 174 and the C-cap module is positioned C-terminal to the ankyrin repeat domain comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 3, 103, 172, and 175.
5. A binding protein comprising an IL4-binding ankyrin repeat domain having the amino acid sequence of SEQ ID NO: 184, an IL13-binding ankyrin repeat domain having the amino acid sequence of SEQ ID NO: 185, and a linker.
6. The binding protein of claim 5 , wherein the binding protein binds to IL4 or IL13 with a K D value of less than 2 nM as determined by surface plasmon resonance.
7. The binding protein of claim 5 , wherein the linker is a GS linker.
8. A binding protein comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 41, 104, 177, and 178.
9. A binding protein comprising a binding domain, an amino terminal cap (N-cap) module and a carboxy terminal cap (C-cap) module, wherein the binding protein binds to human IL4 and inhibits human IL4 binding to IL4Ralpha in vitro or in vivo, and the binding domain is an ankyrin repeat domain and comprises an ankyrin repeat (AR1) module positioned C-terminal to the N-cap module comprising the amino acid sequence of SEQ ID NOS: 39 or 88, an ankyrin repeat (AR2) module positioned C-terminal to the AR1 module comprising the amino acid sequence of SEQ ID NOS: 89 or 180, and an ankyrin repeat (AR3) module positioned C-terminal to the AR2 module comprising the amino acid sequence of SEQ ID NO: 181 and wherein the N-cap module is positioned N-terminal to the ankyrin repeat domain and the C-cap module is positioned C-terminal to the ankyrin repeat domain.
10. A binding protein comprising a binding domain, an amino terminal cap (N-cap) module and a carboxy terminal cap (C-cap) module, wherein the binding domain is an ankyrin repeat domain and binds to human IL13 in vitro or in vivo, inhibiting human IL13 binding to at least one of human IL13Ralpha1 and human IL13Ralpha2, and wherein the binding protein comprises an ankyrin repeat (AR1) module positioned C-terminal to the N-cap module comprising the amino acid sequence of SEQ ID NOS: 108 or 109, an ankyrin repeat (AR2) module positioned C-terminal to the AR1 module comprising the amino acid sequence of SEQ ID NOS: 126, 158, 159, or 182, and an ankyrin repeat (AR3) module positioned C-terminal to the AR2 module comprising the amino acid sequence of SEQ ID NO: 183 and wherein the N-cap module is positioned N-terminal to the ankyrin repeat domain and the C-cap module is positioned C-terminal to the ankyrin repeat domain.