Anti-DLL4/VEGF dual variable domain immunoglobulin and uses thereof
First Claim
Patent Images
1. A binding protein comprising first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, whereinVD1 is a first variable domain;
- VD2 is a second variable domain;
C is a constant domain;
X1 is a linker;
X2 is an Fc region;
n is 0 or 1,wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site, and wherein the binding protein is capable of binding DLL4 and VEGF, wherein the first polypeptide chain of the binding protein comprises SEQ ID NO;
56 and the second polypeptide chain of the binding protein comprises SEQ ID NO;
64.
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Abstract
Disclosed herein are multivalent and multispecific binding proteins, methods of making the binding proteins, and their uses in the diagnosis, monitoring, inhibition, prevention and/or treatment of cancers, tumors, and/or other angiogenesis-dependent diseases characterized by aberrant DLL4 and/or VEGF expression or activity.
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Citations
11 Claims
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1. A binding protein comprising first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, wherein
VD1 is a first variable domain; -
VD2 is a second variable domain; C is a constant domain; X1 is a linker; X2 is an Fc region; n is 0 or 1, wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site, and wherein the binding protein is capable of binding DLL4 and VEGF, wherein the first polypeptide chain of the binding protein comprises SEQ ID NO;
56 and the second polypeptide chain of the binding protein comprises SEQ ID NO;
64.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
VD2 is a second heavy chain variable domain; C is a heavy chain constant domain; X1 is a linker; X2 is an Fc region; n is 0 or 1, and wherein the binding protein comprises a second polypeptide chain comprising a second VD1-(X1)n-VD2-C-(X2)n, wherein VD1 is a first light chain variable domain; VD2 is a second light chain variable domain; C is a light chain constant domain; X1 is a linker; n is 0 or 1 for (X1)n; n is 0 for (X2)n, wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site.
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3. The binding protein of claim 1, wherein the binding protein comprises two first and two second polypeptide chains and four functional target binding sites.
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4. The binding protein of claim 1, wherein the binding protein is capable of binding:
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(a) VEGF with a dissociation constant (KD) of at most about 7.40×
10−
9M, as measured by surface plasmon resonance; and
/or(b) DLL4 with a dissociation constant (KD) of at most about 3.40×
10−
8 M or 5.00×
10−
8 M, as measured by surface plasmon resonance.
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5. The binding protein of claim 1, wherein the Fc region of the binding protein is an Fc region from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD, or a variant thereof.
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6. The binding protein of claim 1, wherein the Fc region of the binding protein is a variant sequence Fc region.
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7. The binding protein of claim 1, wherein the binding protein comprises the constant region sequences from SEQ ID NO:
- 73 and/or SEQ ID NO;
74.
- 73 and/or SEQ ID NO;
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8. The binding protein of claim 1, wherein the first and second polypeptide chains of the binding protein comprise SEQ ID NOs:
- 74 and 73.
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9. The binding protein of claim 8, wherein the binding protein is capable of:
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(a) binding to VEGF with a dissociation constant (KD) of at most about 7.0×
10−
10 M, as measured by surface plasmon resonance, and/or blocking VEGF activity with an IC50 of at most about 3.8 nM, as measured in a VEGFR1 Competition ELISA; and
/or(b) binding to DLL4 with a dissociation constant (KD) of at most about 1.0×
10−
8 M, as measured by surface plasmon resonance, and/or blocking DLL4 activity with an IC50 of at most about 1.09 nM, as measured in a Notch Competition ELISA.
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10. A composition comprising the binding protein of claim 1 and at least one additional agent.
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11. The composition of claim 10, wherein the at least one additional agent comprises one or more of a cytotoxic agent, a chemotherapeutic agent, an anti-angiogenic agent, an anti-CTLA4 antibody, a calcium channel blocker, an ACE inhibitor, FOLFIRI, paclitaxel, carboplatin, doxil, topotecan, and cisplatin.
Specification