Inhibitors of receptor tyrosine kinases and methods of use thereof
The present invention provides moieties that bind to an Ig-like domain, e.g., D4 or D5, of a human receptor tyrosine kinase, e.g., the human Kit RTK or the PDGFR RTK, or the D7 domain of a type V receptor tyrosine kinase wherein the moieties lock the ectodomain of the receptor tyrosine kinase in an inactive state thereby antagonizing the activity of the receptor tyrosine kinase.
1. An antibody, or antigen-binding portion thereof, that binds to the human KIT receptor (SEQ ID NO:92), wherein said antibody, or antigen-binding portion thereof, is a humanized antibody or antigen-binding portion thereof, a human antibody or antigen-binding portion thereof, or a chimeric antibody or antigen-binding portion thereof, and wherein said antibody, or antigen-binding portion thereof, binds to a sequence consisting of amino acid residues 375-391 of the human KIT receptor (SEQ ID NO:92).
2. The An antibody, or antigen-binding portion thereof, that binds to the human KIT receptor (SEQ ID NO:92), wherein the antibody, or antigen-binding portion thereof, is a humanized antibody or antigen-binding portion thereof, a human antibody or antigen-binding portion thereof, or a chimeric antibody or antigen-binding portion thereof, and wherein the antibody, or antigen-binding portion thereof, binds to a sequence consisting of LX 1 RX 2 X 3 X 4 X 5 X 6 X 7 G (SEQ ID NO:158) wherein L is Leucine, R is Arginine, G is Glycine; X 1 is Threonine; X2 is Leucine; X 3 is Lysine; X 4 is Glycine; X 5 is Threonine; X 6 is Glutamic Acid; and X 7 is Glycine.
3. The antibody, or antigen-binding portion thereof, of claim 1 or claim 2 , wherein said antibody, or antigen-binding portion thereof, comprises a heavy chain constant region selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE constant regions.
4. The antibody, or antigen-binding portion thereof, of claim 3 , wherein the antibody heavy chain constant region is IgG1.
5. The antibody, or antigen-binding portion thereof, of claim 1 or claim 2 , wherein said antibody, or antigen-binding portion thereof, is selected from the group consisting of a Fab fragment, a F(ab') 2 fragment, a single chain Fv fragment, an SMIP, an affibody, an avimer, a nanobody, and a single domain antibody.
6. The antibody, or antigen-binding portion thereof, of claim 1 or claim 2 , wherein said antibody, or antigen-binding portion thereof, binds to the human KIT receptor (SEQ ID NO:92) with a KD selected from the group consisting of 1 ×10 −7 M or less, 5×10 −8 M or less, 1 ×10 −8 M or less, and 5 ×10 −9 M or less.
7. The antibody, or antigen-binding portion thereof, of claim 1 or claim 2 , wherein the antibody, or antigen-binding portion thereof, binds to all of the amino acid residues recited therein.
8. The antibody, or antigen-binding portion thereof, of claim 1 or claim 2 , wherein the antibody, or antigen-binding portion thereof, is a humanized antibody, or antigen-binding portion thereof.
9. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 1 or claim 2 and a pharmaceutically acceptable carrier.