Bispecific, bivalent anti-VEGF/anti-ANG-2 antibodies

#This application claims priority to and the benefit of European Application No. 10003269.7 filed Mar. 26, 2010, the contents of which is incorporated herein by reference.

#The present invention relates to bispecific, bivalent antibodies against human vascular endothelial growth factor (VEGF/VEGF-A) and against human angiopoietin-2 (ANG-2), methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.

#Angiogenesis is implicated in the pathogenesis of a variety of disorders which include solid tumors, intraocular neovascular syndromes such as proliferative retinopathies or age-related macular degeneration (AMD), rheumatoid arthritis, and psoriasis (Folkman, J., et al., J. Biol. Chem. 267 (1992) 10931-10934; Klagsbrun, M., et al., Annu Rev. Physiol. 53 (1991) 217-239; and Garner, A., Vascular diseases, in: Pathobiology of ocular disease, A dynamic approach, Garner, A., and Klintworth, G. K. (eds.), 2nd edition, Marcel Dekker, New York (1994), pp. 1625-1710). In the case of solid tumors, the neovascularization allows the tumor cells to acquire a growth advantage and proliferative autonomy compared to the normal cells. Accordingly, a correlation has been observed between density of microvessels in tumor sections and patient survival in breast cancer as well as in several other tumors (Weidner, N., et al., N Engl J. Med. 324 (1991) 1-8; Horak, E. R., et al., Lancet 340 (1992) 1120-1124; and Macchiarini, P., et al., Lancet 340 (1992) 145-146).

#FIG. 1 Exemplary bivalent bispecific antibody format for XMab examples including Knobs-into-Holes modified CH3 domains

#FIG. 2a Exemplary bivalent bispecific antibody format for OAscFab examples including Knobs-into-Holes modified CH3 domains

#FIG. 2b Exemplary bivalent bispecific antibody format for example OAscXFab1 including Knobs-into-Holes modified CH3 domains

#The invention is directed to a bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2. characterized in that i) said first antigen-binding site comprises as heavy chain variable domain (VH) the SEQ ID NO: 1, and as light chain variable domain (VL) the SEQ ID NO: 2; and ii) said second antigen-binding site comprises as heavy chain variable domain (VH) the SEQ ID NO: 3, and as light chain variable domain (VL) the SEQ ID NO: 4.

#In one aspect of the invention the bispecific antibody according to the invention is characterized in comprising a) the heavy chain and the light chain of a first full length antibody that specifically binds to VEGF; b) the modified heavy chain and modified light chain of a full length antibody that specifically binds to ANG-2, wherein the constant domains CL and CH1 are replaced by each other.

#This bispecific, bivalent antibody format for the bispecific antibody specifically binding to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is described in WO 2009/080253 (see exemplary scheme in including Knobs-into-Holes modified CH3 domains in FIG. 1). The antibodies based on this bispecific, bivalent antibody format are named XMab in the examples of the current invention.