Loading patent…
AssigneeGenentech, Inc.
InventorsManuel Baca, James A. Wells, Leonard G. Presta, Henry B. Lowman, Yvonne Man-yee Chen
Estimating the term…
Humanized and variant anti-VEGF antibodies and various uses therefor are disclosed. The anti-VEGF antibodies have strong binding affinities for VEGF; inhibit VEGF-induced proliferation of endothelial cells in vitro; and inhibit tumor growth in vivo.
A humanized anti-vascular endothelial growth factor (VEGF) antibody which binds human VEGF with a Kd value of no more than about 1×10−8M.
A humanized anti-vascular endothelial growth factor (VEGF) antibody which binds human VEGF with a Kd value of no more than about 5×10−9M.
A humanized anti-vascular endothelial growth factor (VEGF) antibody which has an ED50 value of no more than about 5 nM for inhibiting VEGF-induced proliferation of endothelial cells in vitro.
A humanized anti-vascular endothelial growth factor (VEGF) antibody which inhibits VEGF-induced angiogenesis in vivo.
An anti-VEGF antibody light chain variable domain comprising the amino acid sequence:
An anti-VEGF antibody heavy chain variable domain comprising the amino acid sequence:
A variant of a parent anti-vascular endothelial growth factor (VEGF) antibody, wherein said variant binds human VEGF and comprises an amino acid substitution in a complementarity determining region (CDR) of a heavy chain variable domain of said parent antibody.
Dependencies are inferred from the claim text.
From the US filing history. Foreign family members aren’t listed.
Backward citations are indexed for grants only.
Against material from animals or humans: against growth factors ; against growth regulators
Antineoplastic agents
Medicinal preparations containing antigens or antibodies: comprising antibodies
Characterized by taxonomic origin: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
Term end not estimated
1. Field of the Invention
This invention relates generally to anti-VEGF antibodies and, in particular, to humanized anti-VEGF antibodies and variant anti-VEGF antibodies.
2. Description of Related Art
FIGS. 1A and 1B depict the amino acid sequences of variable heavy domain (SEQ ID NO: 9) and light domain (SEQ ID NO: 10) of muMAbVEGF A.4.6.1, variable heavy domain (SEQ ID NO: 7) and light domain (SEQ ID NO: 8) of humanized F(ab) (F(ab)-12) and human consensus frameworks (hum III for heavy subgroup III (SEQ ID NO: 11); humκ1 for light κ subgroup I (SEQ ID NO: 12)). FIG. 1A aligns variable heavy domain sequences and FIG. 1B aligns variable light domain sequences. Asterisks indicate differences between humanized F(ab)-12 and the murine MAb or between F(ab)-12 and the human framework. Complementarity Determining Regions (CDRs) are underlined.
FIG. 2 is a ribbon diagram of the model of humanized F(ab)-12 VL and VH domains. VL domain is shown in brown with CDRs in tan. The sidechain of residue L46 is shown in yellow. VH domain is shown in purple with CDRs in pink. Sidechains of VH residues changed from human to murine are shown in yellow.
FIG. 3 depicts inhibition of VEGF-induced mitogenesis by humanized anti-VEGF F(ab)-12 from Example 1. Bovine adrenal cortex-derived capillary endothelial cells were seeded at the density of 6×103 cells/well in six well plates, as described in Example 1. Either muMAb VEGF A.4.6.1 or rhuMAb VEGF (IgG1; F(ab)-12) was added at the indicated concentrations. After 2-3 hours, rhVEGF165 was added at the final concentration of 3 ng/ml. After five or six days, cells were trypsinized and counted. Values shown are means of duplicate determinations. The variation from the mean did not exceed 10%.
I. Definitions
The term “human VEGF” as used herein refers to the 165-amino acid human vascular endothelial cell growth factor, and related 121-, 189-, and 206-amino acid vascular endothelial cell growth factors, as described by Leung et al., Science 246:1306 (1989), and Houck et al., Mol. Endocrin. 5:1806 (1991) together with the naturally occurring allelic and processed forms of those growth factors.
The present invention provides anti-VEGF antagonistic antibodies which are capable of inhibiting one or more of the biological activities of VEGF, for example, its mitogenic or angiogenic activity. Antagonists of VEGF act by interfering with the binding of VEGF to a cellular receptor, by incapacitating or killing cells which have been activated by VEGF, or by interfering with vascular endothelial cell activation after VEGF binding to a cellular receptor. All such points of intervention by a VEGF antagonist shall be considered equivalent for purposes of this invention.