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To fully assess the role of VEGF-A in tumor angiogenesis, antibodies that can block all sources of vascular endothelial growth factor (VEGF) are desired. Selectively targeting tumor-derived VEGF overlooks the contribution of host stromal VEGF. Other strategies, such as targeting VEGF receptors directly or using receptor decoys, result in inhibiting not only VEGF-A but also VEGF homologues (e.g. placental growth factor, VEGF-B, and VEGF-C), which may play a role in angiogenesis. Here we report the identification of novel anti-VEGF antibodies, B20 and G6, from synthetic antibody phage libraries, which block both human and murine VEGF action in vitro. Their affinity-improved variants completely inhibit three human tumor xenografts in mice of skeletal muscle, colorectal, and pancreatic origins (A673, HM-7, and HPAC). Avastin, which only inhibits the tumor-derived human VEGF, is ∼90% effective at inhibiting HM-7 and A673 growth but is <50% effective at inhibiting HPAC growth. Indeed, HPAC tumors contain more host stroma invasion and stroma-derived VEGF than other tumors. Thus, the functional contribution of stromal VEGF varies greatly among tumors, and systemic blockade of both tumor and stroma-derived VEGF is sufficient for inhibiting the growth of tumor xenografts. To fully assess the role of VEGF-A in tumor angiogenesis, antibodies that can block all sources of vascular endothelial growth factor (VEGF) are desired. Selectively targeting tumor-derived VEGF overlooks the contribution of host stromal VEGF. Other strategies, such as targeting VEGF receptors directly or using receptor decoys, result in inhibiting not only VEGF-A but also VEGF homologues (e.g. placental growth factor, VEGF-B, and VEGF-C), which may play a role in angiogenesis. Here we report the identification of novel anti-VEGF antibodies, B20 and G6, from synthetic antibody phage libraries, which block both human and murine VEGF action in vitro. Their affinity-improved variants completely inhibit three human tumor xenografts in mice of skeletal muscle, colorectal, and pancreatic origins (A673, HM-7, and HPAC). Avastin, which only inhibits the tumor-derived human VEGF, is ∼90% effective at inhibiting HM-7 and A673 growth but is <50% effective at inhibiting HPAC growth. Indeed, HPAC tumors contain more host stroma invasion and stroma-derived VEGF than other tumors. Thus, the functional contribution of stromal VEGF varies greatly among tumors, and systemic blockade of both tumor and stroma-derived VEGF is sufficient for inhibiting the growth of tumor xenografts. Targeting angiogenesis, the process of new blood vessel formation, has been validated as an effective approach for cancer therapy by the recent Food and Drug Administration approval of bevacizumab (Avastin™ antibody), a blocking antibody against vascular endothelial growth factor A (VEGF-A or VEGF), 5The abbreviations used are: VEGFvascular endothelial growth factorh-VEGFhuman VEGFm-VEGFmurine VEGFVEGFRVEGF receptorPlGFplacental growth factorFabantigen binding fragmentELISAenzyme-linked immunosorbent assayECDextracellular domainBSAbovine serum albuminHRPhorseradish peroxidasePBSphosphate-buffered salineCHAPS3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acidHUVEChuman umbilical vein endothelial cellsCDRcomplementarity determining region. for the treatment of metastatic colorectal cancer (1Hurwitz H. Fehrenbacher L. Novotny W. Cartwright T. Hainsworth J. Heim W. Berlin J. Baron A. Griffing S. Holmgren E. Ferrara N. Fyfe G. Rogers B. Ross R. Kabbinavar F. N. Engl. J. Med. 2004; 350: 2335-2342Crossref PubMed Scopus (9270) Google Scholar, 2Ferrara N. Hillan K.J. Gerber H.P. Novotny W. Nat. Rev. Drug Discov. 2004; 3: 391-401Crossref PubMed Scopus (2132) Google Scholar). Although many pro- or anti-angiogenic factors have been implicated in tumor angiogenesis (3Hanahan D. Christofori G. Naik P. Arbeit J. Eur. J. Cancer. 1996; 32: 2386-2393Abstract Full Text PDF Scopus (220) Google Scholar, 4Yancopoulos G.D. Davis S. Gale N.W. Rudge J.S. Wiegand S.J. Holash J. Nature. 2000; 407: 242-248Crossref PubMed Scopus (3298) Google Scholar), the efficacy of a specific blocking antibody against VEGF in suppressing cancer progression emphasizes the key role of VEGF. However, as VEGF is a member of a family that also includes VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF) with overlapping activities in three tyrosine kinase receptors, VEGFR1 (Flt-1), VEGFR2 (KDR, or Flk-1 in mouse), and VEGFR3 (5Shibuya M. Ito A. Claesson Welsh L. Curr. Top. Microbiol. Immunol. 1999; 237: 59-83PubMed Google Scholar, 6Ferrara N. Endocr. Rev. 2004; 25: 581-611Crossref PubMed Scopus (3009) Google Scholar), the questions whether VEGF-A has a nonredundant role in tumor angiogenesis and whether blocking VEGF-A is sufficient to inhibit tumor growth are fundamental. vascular endothelial growth factor human VEGF murine VEGF VEGF receptor placental growth factor antigen binding fragment enzyme-linked immunosorbent assay extracellular domain bovine serum albumin horseradish peroxidase phosphate-buffered saline 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acid human umbilical vein endothelial cells complementarity determining region. Systemic blockade using specific blocking antibodies against tumor-derived VEGF (7Kim K.J. Li B. Winer J. Armanini M. Gillett N. Phillips H.S. Ferrara N. Nature. 1993; 362: 841-844Crossref PubMed Scopus (3363) Google Scholar) or genetic deletion of VEGF in tumor cells (8Shi Y.P. Ferrara N. Biochem. Biophys. Res. Commun. 1999; 254: 480-483Crossref PubMed Scopus (34) Google Scholar, 9Grunstein J. Roberts W.G. Mathieu-Costello O. Hanahan D. Johnson R.S. Cancer Res. 1999; 59: 1592-1598PubMed Google Scholar, 10Inoue M. Hager J.H. Ferrara N. Gerber H.P. Hanahan D. Cancer Cell. 2002; 1: 193-202Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar) severely suppressed tumor growth in mouse models. However, residual growth or resistance of human tumor xenografts in nude mice treated with antibodies against human VEGF has been reported (7Kim K.J. Li B. Winer J. Armanini M. Gillett N. Phillips H.S. Ferrara N. Nature. 1993; 362: 841-844Crossref PubMed Scopus (3363) Google Scholar, 11Gerber H.P. Kowalski J. Sherman D. Eberhard D.A. Ferrara N. Cancer Res. 2000; 60: 6253-6258PubMed Google Scholar). One possibility is that residual tumor angiogenesis and growth are supported by murine VEGF, which is produced by host stromal cells recruited into the tumor (11Gerber H.P. Kowalski J. Sherman D. Eberhard D.A. Ferrara N. Cancer Res. 2000; 60: 6253-6258PubMed Google Scholar). Significant VEGF expression has been demonstrated by fibroblast and immune cells that surround and invade the tumor mass (12Hlatky L. Tsionou C. Hahnfeldt P. Coleman C. Cancer Res. 1994; 54: 6083-6086PubMed Google Scholar, 13Fukumura D. Xavier R. Sugiura T. Chen Y. Park E.C. Lu N. Selig M. Nielsen G. Taksir T. Jain R.K. Seed B. Cell. 1998; 94: 715-725Abstract Full Text Full Text PDF PubMed Scopus (847) Google Scholar, 14Kishimoto J. Ehama R. Ge Y. Kobayashi T. Nishiyama T. Detmar M. Burgeson R.E. Am. J. Pathol. 2000; 157: 103-110Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 15Coussens L.M. Raymond W.W. Bergers G. Laig-Webster M. Behrendtsen O. Werb Z. Caughey G.H. Hanahan D. Genes Dev. 1999; 13: 1382-1397Crossref PubMed Scopus (808) Google Scholar, 16Barbera-Guillem E. Nyhus J.K. Wolford C.C. Friece C.R. Sampsel J.W. Cancer Res. 2002; 62: 7042-7049PubMed Google Scholar), although the significance and extent of the contribution of such stroma-derived VEGF to tumor growth remain unclear. Other possible explanations for incomplete tumor growth inhibition following treatment with anti-VEGF antibodies include the following: insufficient binding affinity or tumor penetration; VEGF-related molecules (e.g. PlGF and VEGF-C) that may act independently or in concert with VEGF-A in promoting angiogenesis (17Autiero M. Waltenberger J. Communi D. Kranz A. Moons L. Lambrechts D. Kroll J. Plaisance S. De Mol M. Bono F. Kliche S. Fellbrich G. Ballmer-Hofer K. Maglione D. Mayr-Beyrle U. Dewerchin M. Dombrowski S. Stanimirovic D. Van Hummelen P. Dehio C. Hicklin D.J. Persico G. Herbert J.M. Shibuya M. Collen D. Conway E.M. Carmeliet P. Nat. Med. 2003; 9: 936-943Crossref PubMed Scopus (656) Google Scholar); VEGF-independent angiogenesis pathways; and “vascular mimicry” by tumor cells (18Hendrix M.J. Seftor E.A. Hess A.R. Seftor R.E. Nat. Rev. Cancer. 2003; 3: 411-421Crossref PubMed Scopus (710) Google Scholar). To address these issues, some of us (11Gerber H.P. Kowalski J. Sherman D. Eberhard D.A. Ferrara N. Cancer Res. 2000; 60: 6253-6258PubMed Google Scholar) and others (19Kim E.S. Serur A. Huang J. Manley C.A. McCrudden K.W. Frischer J.S. Soffer S. Ring L. New T. Zabski S. Rudge J.S. Holash J. Yancopoulos G.D. Kandel J.J. Yamashiro D.J. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11399-11404Crossref PubMed Scopus (297) Google Scholar) have used the soluble VEGF receptor extracellular domain (ECD) fragment, such as VEGFR1 Ig domain 1-3 Fc fusion (VEGFR1D1-3-Fc) or VEGF trap (VEGFR1D2-VEGFR2D3-Fc), and showed more inhibition of human xenografts to antibodies against tumor-derived VEGF. that these receptor can block both human and murine VEGF (11Gerber H.P. Kowalski J. Sherman D. Eberhard D.A. Ferrara N. Cancer Res. 2000; 60: 6253-6258PubMed Google Scholar) or that the receptor have affinity than the antibody (19Kim E.S. Serur A. Huang J. Manley C.A. McCrudden K.W. Frischer J.S. Soffer S. Ring L. New T. Zabski S. Rudge J.S. Holash J. Yancopoulos G.D. Kandel J.J. Yamashiro D.J. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11399-11404Crossref PubMed Scopus (297) Google Scholar). However, these receptor may also block other VEGF family and Although deletion of D. C.A. M. A. S. C. M. N. Res. 2000; PubMed Google Scholar) or PlGF P. Moons L. A. De Mol M. Y. Bono F. L. H. D. T. T. Dewerchin M. A. A. S. T. A. U. J.M. W. Hicklin D.J. Herbert J.M. Collen D. Persico Nat. Med. PubMed Scopus Google Scholar) in and that these factors are not for angiogenesis, recent have that both and PlGF can to angiogenesis P. Moons L. A. De Mol M. Y. Bono F. L. H. D. T. T. Dewerchin M. A. A. S. T. A. U. J.M. W. Hicklin D.J. Herbert J.M. Collen D. Persico Nat. Med. 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J. 2004; PubMed Scopus Google Scholar). the used antibodies from the human of antibody with phage is in process that to the G. R.E. Rev. Immunol. 1994; PubMed Scopus Google Scholar, 2002; Google Scholar). we report the identification of and murine VEGF binding and the affinity-improved and B20 variants for binding and VEGF blocking activities in to the the and we variants for in and inhibiting action in to Avastin, and to anti-VEGF antibodies the specific role of VEGF in the tumor progression using mouse models. of and used to the binding affinity of phage anti-VEGF to and as C. G. J. 2004; PubMed Scopus Google Scholar). phage with of or in with and for and phage with and by phage antibody with horseradish peroxidase by the of VEGF with phage in that effective in binding of phage to block binding to VEGF from the of the expression the of and and with the affinity as C. G. J. 2004; PubMed Scopus Google Scholar). with and with A affinity binding VEGF and homologues an at in and with and of or in VEGF for and with antibody in VEGF mouse and human human VEGF-C, mouse VEGF-D, human and mouse VEGF-B, from binding also in some the or with VEGF homologues at for and the antibodies with and as with the binding VEGF blocking by phage with of receptor for and phage phage as and used to receptor blocking VEGF by VEGFR2 domain as fusion with the VEGFR1 fragment or with anti-VEGF antibodies in of at the to a VEGF and for VEGF-A with VEGF and by as binding affinity with with and to the or murine VEGF to of or in with at or not at a of and using binding as the of VEGF umbilical vein endothelial cells and as G. Li B. C. B. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). in of the and in with bovine serum for assay with of VEGF which as a of VEGF that can and of anti-VEGF antibodies to the at for cells with of for and for with and in and HPAC cells in with with bovine at in and and in at a of in mice by of and to tumors a of for HM-7 and for A673 and HPAC a as mice into of and antibodies at the for and as (11Gerber H.P. Kowalski J. Sherman D. Eberhard D.A. Ferrara N. Cancer Res. 2000; 60: 6253-6258PubMed Google Scholar). used and in for to of with and as H.P. Hillan K.J. Kowalski J. L. F. M. Ferrara N. 1999; PubMed Google Scholar). in of tumors, as M. G. N. E. Ferrara N. J. 2004; PubMed Scopus Google Scholar). three from the tumor for VEGF in and in VEGF in tumors, of tumor in and and VEGF of as C.R. B. J. Immunol. 1998; PubMed Scopus Google Scholar). used antibody to as and as in and by not To used antibody as and the antibody in the for in and tumor in by of at serum anti-VEGF with in and with of serum or anti-VEGF for and Avastin, for and for in bovine in for antibodies by for Avastin, and as human and for which mouse antibodies and with with antibodies as antibodies with the antibodies with using the assay for we that serum from nude mice with antibodies than mouse and B20 and and B20 among from a synthetic antibody phage with as the by against binding and receptor blocking of these phage the fragment G6, the with the affinity for also showed binding for at and with affinity of and To assess which antibody can block VEGF binding to receptors, VEGFR2 with or the Ig domain of VEGFR1 used to block the of phage with blocking with and B20 by both receptor that VEGF with the for receptor B20 and affinity for and a of affinity by in a with for both and and to the binding and as demonstrated affinity for human and murine VEGF for and binding to other VEGF and not and not also and VEGF with affinity as for not receptor blocking of or by blocking both and binding to VEGFR2 Ig domain or VEGFR1 Ig domain blocking for VEGFR2 binding and the is not in can only block but not binding to the receptor as with affinity for showed at as a binding affinity for Y. C. G. Li B. P. J. 1999; PubMed Scopus Google Scholar) binding and of anti-VEGF antibodies of or are using with human or murine VEGF at and an of three that by binding not in a new and B20 the affinity of G6, as C. G. J. 2004; PubMed Scopus Google Scholar). variants that from by or in the and by in to of the variants as or at with human or murine VEGF in to as and the affinity-improved by the the but the of these antibodies and B20 variants have for human and murine VEGF. with as with affinity as and as and of and used with in the as have activities in and in Chen H. S.J. L. M. Ferrara N. Cancer Res. Google Scholar). the affinity and than but variants with and than for binding binding for of the VEGF homologues VEGF-B, and as However, as but not as some with the of the To assess whether binding to is we inhibits from binding and we inhibition at as binding for the and block both and from binding VEGFR2 and VEGFR1 with and and not of and not play a role for in the of and B20 variants in inhibiting the growth of and and B20 affinity-improved variants to inhibit the of both human and murine VEGF, or Avastin, as human VEGF as in inhibiting and more than in inhibiting human and murine VEGF and more than in inhibiting with binding and to the assay to antibodies with than the of VEGF used in the assay of and with and in in whether a more blockade of VEGF tumor or into nude mice the human colorectal cancer HM-7 a tumor the mouse that not block VEGF from and in the for at of or and for tumor and tumor at the of the antibodies tumors to the in a to inhibit tumor growth at the in tumor of vessel inhibition of angiogenesis as the of action To whether a binding affinity and of tumor the affinity antibody with the affinity antibodies have that both antibodies tumor inhibition at the However, at and effective than and that affinity may result in in with and not in binding for and more than a for in inhibiting endothelial growth in all tumor in the not than the only that showed a of the but the not One possible is that stromal VEGF and the of blocking tumor-derived VEGF. that have some binding affinity for has binding to the of the possible is that the the of VEGF not the of these antibodies to the and in in VEGF the of stromal VEGF contribution to tumor we the efficacy of antibodies that both stromal and tumor-derived VEGF, and and antibodies that only tumor VEGF, a pancreatic tumor which stromal and N. and human A673 HPAC and A673 tumor inhibition with HM-7 at a of these antibodies HM-7 the binding antibodies and more than the antibodies but the inhibition by the some but contribution of stromal VEGF the inhibition by the antibodies not than Avastin, contribution by stromal VEGF than of the HPAC both and completely the tumor more stromal VEGF contribution in the growth of HPAC than HM-7 and A673 A and inhibition of HPAC and HM-7 also effective than the antibodies, but with significance in HPAC but not HM-7, which to the that also in efficacy Avastin, which and the antibodies that VEGF to the tumor growth for the demonstrated that in the of stromal VEGF contribution in the growth of tumors. for the of the antibodies these tumors with of stromal VEGF the of the HM-7 and HPAC tumors treated with the of or antibodies showed that not effective in the tumor and the of of treatment in in both HPAC and HM-7 tumor HM-7 and HPAC HM-7 is a mass of tumor cells with which to only with endothelial treatment with in of these and of to of stromal and host with in a mass by the HM-7 tumor by from the of A673 to HM-7, as (11Gerber H.P. Kowalski J. Sherman D. Eberhard D.A. Ferrara N. Cancer Res. 2000; 60: 6253-6258PubMed Google Scholar). HPAC tumors, with cells and and treatment not result in the tumor to a but the tumor cells the a of to the tumors. of host cells more a of HPAC than VEGF by or and in the of tumor host stroma-derived VEGF in the tumor mass to whether with tumor inhibition by antibodies of the tumor of HM-7 tumor-derived although stroma-derived at a and HPAC tumors of and with the that blocking at inhibiting the growth of HM-7 and A673 but not sufficient for HPAC inhibition for of antibodies in the mice to the to serum the of treatment of the HPAC with for antibody for and for or antibody for and for which of the serum of with the other tumors. of and than for is but is possible that the antibodies, or by host VEGF in the and in are to the and of these antibodies in the of the efficacy of antibodies, the of and antibodies the of the role of affinity in and efficacy using these antibodies, and the of and with and the result that antibodies efficacy than and in of three tumor anti-VEGF antibody three in the HPAC and as and the and of all antibodies are of are than all three other antibodies the of VEGF antibodies, and are in a new genetic and have been to inhibit VEGF and to the key role of VEGF in tumor angiogenesis Ferrara N. Cancer Res. Google Scholar, R.K. 2002; PubMed Scopus Google Scholar). in to or not of the contribution of VEGF-A to tumor angiogenesis (7Kim K.J. Li B. Winer J. Armanini M. Gillett N. Phillips H.S. Ferrara N. Nature. 1993; 362: 841-844Crossref PubMed Scopus (3363) Google Scholar, 11Gerber H.P. Kowalski J. Sherman D. Eberhard D.A. Ferrara N. Cancer Res. 2000; 60: 6253-6258PubMed Google Scholar, E.S. Serur A. Huang J. Manley C.A. McCrudden K.W. Frischer J.S. Soffer S. Ring L. New T. Zabski S. Rudge J.S. Holash J. Yancopoulos G.D. Kandel J.J. Yamashiro D.J. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11399-11404Crossref PubMed Scopus (297) Google Scholar). have phage antibodies, and which block both human and mouse VEGF inhibition of the growth of human colorectal cancer and pancreatic cancer cells in of the tumor inhibition as demonstrated by the extent of tumor and the antibody not tumor cells or inhibit endothelial growth with growth factors other than VEGF (e.g. fibroblast growth not the inhibition a of specific inhibition of VEGF. that blocking VEGF-A is sufficient to fully inhibit tumor angiogenesis and tumor growth. is with recent of an pancreatic tumor VEGF expression severely M. Hager J.H. Ferrara N. Gerber H.P. Hanahan D. Cancer Cell. 2002; 1: 193-202Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar). demonstrated that blocking all sources of VEGF at an of sufficient to inhibit tumor progression and validated for the role of VEGF at of in a of tumor in to the of many contribution of host stroma-derived VEGF in the growth of tumors, is a factor in the of the of or genetic of tumor VEGF has been a as to the functional significance of stromal VEGF. to a recent stromal VEGF not to the growth of A. L. M. C. L. J. C. A. R.S. J. J. 2003; PubMed Scopus Google Scholar). in a that used a of mouse the growth of the tumor in mouse by a blocking antibody against VEGF J. J. M. F. G. W. L. Kowalski J. G. Gerber H.P. Ferrara N. 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Sugiura T. Chen Y. Park E.C. Lu N. Selig M. Nielsen G. Taksir T. Jain R.K. Seed B. Cell. 1998; 94: 715-725Abstract Full Text Full Text PDF PubMed Scopus (847) Google Scholar), and the of VEGF from a to angiogenesis is G. R. G. T. K. K. P. S. Werb Z. Hanahan D. Nat. 2000; PubMed Scopus Google Scholar). is that a of VEGF is or in the process of which from tumor to the stromal VEGF to tumor angiogenesis, the of tumor growth also the of VEGF to tumor angiogenesis. of the affinity of antibodies among tumors and tumor models. VEGF in HM-7 have the of the affinity of the blocking to to assess the of binding affinity in to the and efficacy in tumor and and tumor models. blocking anti-VEGF antibodies are to these the that blocking angiogenesis may J. N. Engl. J. Med. PubMed Scopus (220) Google Scholar), of have at the the of tumor angiogenesis D. J. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). that specific VEGF blockade has been to tumor progression in N. Hillan K.J. 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Liang et al. (Tue,) studied this question.
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