Notch-based fusion proteins and uses thereof
This invention provides a method for treating a subject having a tumor and a method for inhibiting angiogenesis in a subject, both comprising administering to the subject an effective amount of a composition of matter comprising the extracellular domain of a Notch receptor protein operably affixed to a half-life-increasing moiety. This invention also provides a composition of matter comprising the extracellular domain of Notch4 receptor protein operably affixed to a half-life-increasing moiety. This invention further provides an article of manufacture. Finally, this invention provides a replicable vector which encodes a polypeptide comprising the extracellular domain of a Notch receptor protein operably affixed to a half-life-increasing moiety, a host vector system which comprises such replicable vector and a method of producing such polypeptide.
1. A fusion protein consisting of consecutive amino acids, the amino acid sequence of which, commencing at the amino terminus, is identical to the amino acid sequence of EGF repeats 1-29 of human Notch4, followed by a linker sequence of amino acids which is followed by an amino acid sequence identical to the sequence of an Fc portion of an antibody, wherein the amino acid sequence of EGF repeats 1-29 of human Notch4 is encoded by the nucleic acid coding sequence of Notch4 EGF repeats 1-29 set forth in SEQ ID NO: 14.
2. The fusion protein of claim 1 , wherein the Fc portion of the antibody is the Fc portion of a human antibody.
3. A fusion protein consisting of consecutive amino acids, the amino acid sequence of which, commencing at the amino terminus, is identical to the amino acid sequence of the EGF repeats of a human Notch receptor protein, followed by a linker sequence of amino acids which is followed by an amino acid sequence identical to the sequence of an Fc portion of an antibody, wherein the amino acid sequence of the EGF repeats of the human Notch receptor protein is selected from the group consisting of: (a) the amino acid sequence of EGF repeats 1-36 of human Notch1 encoded by the nucleic acid coding sequence of Notch1 EGF repeats 1-36 set forth in SEQ ID NO: 11; (b) the amino acid sequence of EGF repeats 1-36 of human Notch2 encoded by the nucleic acid coding sequence of Notch2 EGF repeats 1-36 set forth in SEQ ID NO: 12; and (c) the amino acid sequence of EGF repeats 1-34 of human Notch3 encoded by the nucleic acid coding sequence of Notch3 EGF repeats 1-34 set forth in SEQ ID NO: 13.
4. The fusion protein of claim 3 , wherein the amino acid sequence of the EGF repeats of the human Notch receptor protein is identical to the amino acid sequence of EGF repeats 1-36 of human Notch1 encoded by the nucleic acid coding sequence of Notch1 EGF repeats 1-36 set forth in SEQ ID NO: 11.
5. The fusion protein of claim 3 , wherein the amino acid sequence of the EGF repeats of the human Notch receptor protein is identical to the amino acid sequence of EGF repeats 1-36 of human Notch2 encoded by the nucleic acid coding sequence of Notch2 EGF repeats 1-36 set forth in SEQ ID NO: 12.
6. The fusion protein of claim 3 , wherein the amino acid sequence of the EGF repeats of the human Notch receptor protein is identical to the amino acid sequence of EGF repeats 1-34 of human Notch3 encoded by the nucleic acid coding sequence of Notch3 EGF repeats 1-34 set forth in SEQ ID NO: 13.
7. The fusion protein of claim 3 , wherein the Fc portion of the antibody is the Fc portion of a human antibody.