Light targeting molecules and uses thereof
View Patent ↗LIGHT-targeting molecules (e.g., LIGHT fusion molecules), anti-HER2 antibody molecules, compositions, e.g., pharmaceutical compositions thereof, are disclosed. Methods of using these molecules to treat, prevent and/or diagnose hyperproliferative, e.g., neoplastic, diseases or conditions, including, but not limited to, cancer and metastasis are also provided.
1. A LIGHT-targeting molecule, comprising an extracellular domain of a human LIGHT protein or fragment thereof, and a targeting antibody molecule that binds to HER2, wherein the targeting antibody molecule comprises a heavy chain variable (V H ) amino acid sequence comprising the amino acid sequence of CDR1 (SEQ ID NO:47), CDR2 (SEQ ID NO:48) and CDR3 (SEQ ID NO:49) and a light chain variable (V L ) amino acid sequence comprising the amino acid sequence of CDR1 (SEQ ID NO:74), CDR2 (SEQ ID NO:75) and CDR3 (SEQ ID NO:76), and wherein the targeting antibody molecule is linked to the extracellular domain of the human LIGHT protein or fragment thereof.
2. The LIGHT-targeting molecule of claim 1 , wherein the V H is linked to a heavy chain constant region (C H ), which is linked, with or without a linking group (L), to the extracellular domain of the human LIGHT protein or fragment thereof.
3. The LIGHT-targeting molecule of claim 1 , which comprises a dimer or a trimer of the extracellular domain of the human LIGHT protein or fragment thereof and the targeting antibody molecule.
4. The LIGHT-targeting molecule of claim 3 , wherein the extracellular domain of the LIGHT protein or fragment thereof has one or more LIGHT-associated activities chosen from: (i) binding to one or more LIGHT-receptors; (ii) inducing expression of one or more of chemokines or cytokines, chemokine or cytokine receptors, adhesion molecules, or co-stimulatory molecules; (iii) activating T cells; (iv) recruiting T cells into a tumor, cell or tissue; (v) activating or enhancing tumor-reactive T cell proliferation; (vi) creating a lymphoid-like microenvironment at a tumor cell or tissue; (vii) inducing apoptosis of a tumor cell or tissue; or (viii) stimulating an immune response in a subject.
5. The LIGHT-targeting molecule of claim 4 , wherein the extracellular domain of the human LIGHT protein or fragment thereof comprises amino acids 93to 240 of SEQ ID NO:1 (human LIGHT isoform 1), or an amino sequence at least 90% identical thereto.
6. The LIGHT-targeting molecule of claim 1 , which comprises a linker comprising one, two, three, four or five (G 4 S) 4 (SEQ ID NO:134) repeats.
7. The LIGHT-targeting molecule of claim 6 , comprising a heavy chain having the amino acid sequence of SEQ ID NO:4 and a light chain having the amino acid sequence of SEQ ID NO:109, or an amino acid sequence at least 90% identical to SEQ ID NO:4 or SEQ ID NO:109.
8. The LIGHT-targeting molecule of claim 1 , wherein the V H amino acid sequence comprises the amino acid sequence of SEQ ID NO:11, or an amino acid sequence at least 90% identical thereto.
9. The LIGHT-targeting molecule of claim 1 , wherein the V L amino acid sequence comprises the amino acid sequence of SEQ ID NO:13, or an amino acid sequence at least 90% identical thereto.
10. The LIGHT-targeting molecule of claim 1 , wherein the V H amino acid sequence comprises the amino acid sequence of SEQ ID NO:11, or an amino acid sequence at least 90% identical thereto, and wherein the V L amino acid sequence comprises the amino acid sequence of SEQ ID NO:13, or an amino acid sequence at least 90% identical thereto.
11. The LIGHT-targeting molecule of claim 1 , wherein the V H amino acid sequence comprises the amino acid sequence of SEQ ID NO:11.
12. The LIGHT-targeting molecule of claim 1 , wherein the V L amino acid sequence comprises the amino acid sequence of SEQ ID NO:13.
13. The LIGHT-targeting molecule of claim 1 , wherein the V H amino acid sequence comprises the amino acid sequence of SEQ ID NO:11, and wherein the V L amino acid sequence comprises the amino acid sequence of SEQ ID NO:13.
14. The LIGHT-targeting molecule of claim 1 , wherein the extracellular domain of the LIGHT protein comprises amino acids 93 to 240 of SEQ ID NO:1.
15. A pharmaceutical composition comprising the LIGHT-targeting molecule of claim 7 and a pharmaceutically acceptable carrier.
16. A LIGHT-targeting molecule, comprising an extracellular domain of a human LIGHT protein, and a Fab fragment that binds to HER2, wherein the Fab fragment comprises:
a heavy chain variable (V H ) domain comprising the amino acid sequence of SEQ ID NO:11; and
a light chain variable (V L ) domain comprising the amino acid sequence of SEQ ID NO:13;
and wherein the V H domain is linked to a heavy chain constant region 1 (C H1 ) which is linked to the extracellular domain of a human LIGHT protein comprising amino acids 93 to 240 of SEQ ID NO:1.
17. The LIGHT-targeting molecule of claim 16 , further comprising a linking group which links the C H1 to the extracellular domain of a human LIGHT protein.
18. The LIGHT-targeting molecule of claim 17 , wherein the linking group comprises one, two, three, four or five (G 4 5 ) 4 (SEQ ID NO:134) repeats.
19. The LIGHT-targeting molecule of claim 17 , wherein the linking group comprises amino acids 61 to 92 of SEQ ID NO:1.
20. A LIGHT-targeting molecule, comprising an extracellular domain of a human LIGHT protein, and a Fab fragment that binds HER2, wherein the Fab fragment comprises:
the amino acid sequence of SEQ ID NO:4; and
the amino acid sequence of SEQ ID NO:109;
and wherein the Fab fragment is linked with a linking group to the extracellular domain of a human LIGHT protein comprising amino acids 93 to 240 of SEQ ID NO:1.
21. The LIGHT-targeting molecule of claim 20 , wherein the linking group comprises one, two, three, four or five (G 4 5 ) 4 (SEQ ID NO:134) repeats.
22. The LIGHT-targeting molecule of claim 20 , wherein the linking group comprises amino acids 61 to 92 of SEQ ID NO:1.