(12) INT ERNATIONAL APPLlCATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`2 August 2001 (02.08.2001)
`
`• I Ylll llHlll ~ 111111111111111111 11 llm 11111111111111 WI llElll IOI HI YI
`
`(10) International Publication Number
`WO 01/54723 Al
`
`PCT
`
`(St ) International Patent Classification7:
`39/00, 39/38, GOIN 33153
`
`A61K 39/395.
`
`(74) Agent: SOMERVILLE, Deborah, A.; Kenyon &
`Kenyon, One Broadway, New York, NY 10004 (US).
`
`(21) Internationa l Application Number: PCT/USOl/02839
`
`(22) In ternational Filing Date: 29 January 2001 (29.01.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) P riority Data:
`60/178,791
`09/539,692
`
`28 January 2000 (28.01.2000) US
`31 March 2000 (31.03.2000) US
`
`(71) Applicant (for all designated States except BB, US): SUN(cid:173)
`NYBROOK HEALTH SClENCE CENTER [CA/CA];
`2075 Bayview Avenue, North York, Onrario M4N 3M5
`(CA).
`
`(71) Applican t (for BB only) : IMCLONE SYSTEMS IN(cid:173)
`CORPORATED [US/US]; 180 Varick Street, New York,
`NY 10014 (US).
`
`(72) Inven tor ; and
`:::: (75) Inventor/Applicant (for US only): KERBEL, Robert
`
`--
`---
`= [CA/CA]; 48 Bennington Heights Drive, Toronto, Ontario
`
`M4G 1A9 (CA).
`
`=
`
`;;;;;;;;;;;;; = -;;;;;;;;;;;;; -
`
`(81) Designated States (national): AE. AG, AL, AM, AT, AU,
`AZ, BA, BB, BG. BR, BY, BZ. CA, CH. CN. CR, CU, CZ,
`DE, DK, DM, DZ, EE, ES, FI. GB, GD, GE, OH, GM. HR,
`HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
`LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ.
`NO, NZ, PL, PT, RO. RU, SD, SE, SO, SI, SK, SL, TJ, TM,
`TR, TT, TZ, UA. UG, US, UZ, VN, YU, ZA, 'ZW.
`
`(84) Designa ted States (regional): ARIPO patent (OH, GM,
`KE. LS, MW, MZ, SD, SL, SZ. TZ, UG, 'ZW), Eurasian
`patent (AM, AZ, BY. KG, KZ, MD. RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
`IT, LU, MC. NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, ON, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report
`before the expiration of the lime limit for amending the
`claims and lo be republished in the event of receipt of
`amendments
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`~ -(S-4)_T_i-tle_:_TH_ E_RA_ PE_UT_l_C_ME_T_H_O_D_F_O_R_RE_ D_U_CIN_G_AN_ G-10G- EN- -ES-
`r-
`~ (57) Abstract: A method of controUing or treating an angiogenic dependent condition in a mammal, preferably in a human by ad(cid:173)
`-
`ministering an anti-angiogenic molecule such as an angiogenesis growth factor antagonist. and a chemotherapeutic agent in amounts
`'!"""'! and frequencies effective, in combination, to produce a regression or arrest of said condition while minimizing or preventing signif(cid:173)
`0 preferably in a human, comprising an anti-angiogenic molecule, such as an angiogenesis growth factor antagonist, and a chemothera(cid:173)
`> peutic agent in amounts effective, in combination, to produce a regression or arrest of said condition while minimizing or preventing
`
`= icant toxicity of the chemotherapeutic agent. Also a kit for controlling or treating an angiogenic dependent condition in a mammal,
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`,_.... significant toxicity of the chemotherapeutic agent
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`IS- - -- - - - - -- - I _;.~SJ-II •'I/
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`•I
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`THERAPEUTIC METHOD FOR REDUCING ANGIOGENESIS
`
`The present application claims the benefit of priority from U.S. Provisional
`
`Application No. 60/J 78791, filed on January 28, 2000, which is hereby incorporated in its
`
`5
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`entirety by reference.
`
`Field of the Invention
`
`The present invention relates to the inhibition or prevention of angiogenesisas a means
`
`l 0
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`to control or treat an angiogenic dependent condition, a condition characterized by, or
`
`dependent upon, blood vessel proliferation. The invention further relates to the use of an anti(cid:173)
`
`angiogenic molecule in combination with a chemotherapeutic agent.
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`15
`
`Background of the Invention
`
`Angiogenesis is a highJy complex process of developing new blood vessels that involves
`
`the proliferation and migration of. and tissue infiltration by capillary endothelial cells from pre(cid:173)
`
`existing blood vessels. cell assembly into tubular stmc•~!Tc~. : .)ining of newly forming tubular
`
`assemblies to closed-circuit vascular systems. and maturation of newly formed capillary vessels.
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`20
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`The molecular bases of many of these aspectS are still not understood.
`
`Angiogenesis is important in nonnal physiological processes including embryonic
`
`development. follicular growth. and wound healing. as well as in pathological conditions such as
`
`tumor growth and in non·neoplastic diseases involving abnormal neovasculariz.ation, including
`
`neovascular glaucoma (Folkman, J. and Klagsbrun. M. Science 235:442-447 (1987). Other
`
`25
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`disease states include but are not limited to. neoplastic diseases, including but not limited to solid
`
`tumors, autoinunune diseases and collagen vascular diseases such as. for example, rhewnatoid
`
`arthritis, and ophthalmalogical conditions such as diabetic retinopathy, retrolental fibroplasia and
`
`neovascular glaucoma. Conditions or diseases to which persistent or uncontrolled angiogenesis
`
`contribute have been termed angiogenic dependent or angiogenic associated diseases.
`
`30
`
`One means of controlling such diseases and pathological conditions comprises restricting
`
`the blood supply to those cells involved in mediating or causing the disease or condition. For
`
`example, in the case of neoplastic disease, solid tumors develop to a size of about a few
`
`millimeters, and further growth is not possible, absent angiogenesis within the twnor. In the past,
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`strategies to limit the blood supply to tumors have included occluding blood vessels supplying
`
`portions of organs in which tumors are present Such approaches require the site of the tumor to
`
`be identified and are generally limited to treatment to a single site, or small number of sites. An
`
`additional disadvantage of direct mechanical restriction of a blood supply is that collateral blood
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`5
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`vessels develop, often quite rapidly, restoring the blood supply to the tumor.
`
`Other approaches have focused on the modulation of factors that are involved in the
`
`regulation of angiogenesis. While usually quiescent, vascular endothelial proliferation is highly
`
`regulated, even during angiogenesis. Examples of factors that have been implicated as possible
`
`regulators of angiogenesis in vivo include, but are not limited to, transforming growth factor beta
`
`I 0
`
`(TGFp), acidic and basic fibroblast growth factor (aFGF and bFGF), platelet derived growth
`
`factor (PDGF), and vascular endothelial growth factor (VEGF) (KJagsbrun, M. and D'Amore. P.
`
`(1991) Annual Rev. Physic!. 53: 217-239).
`
`One growth factor of particular interest is VEGF. An endothelial-cell specific mitogen,
`
`VEGF acts as an angiogenesis inducer by specifically promoting the proliferation of endothelial
`
`15
`
`cells. It is a homodimeric glycoprotein consisting of rwo 23 kD sublUlits with snuctural similarity
`to PDGF. Four different monomeric isofonns ofVEGF resulting from alternative splicing of
`
`rn!~ ·..;A ·. ·:: been ident11i1::! Tliese include two membrane bound forms (VEGF:?06 and V£Gf18q)
`··.•
`· ·~ form~•· · ·
`:!nd VEGF121 ). VEGF10~ is the most abundant isoform in all
`
`hum~1 : .. ·:-.ucs c?Xcept ,
`
`.
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`20
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`\ l.:uF is exprc:.~~·..
`
`·· ::mbryonic tissues (Breier et al.. Development (Camb.) 114:521
`
`( 1992)), macrophages. and proliferating epidermal keratinocytes during wound healing (Brown et
`
`al .. J. Exp. Med., 176: 1375 ( 1992)). and may be responsible for tissue edema associated with
`
`inflammation (Ferrara et al.. Endocr. Rev. 13: 18 ( 1992)). In situ hybridization studies have
`
`demonstrated high levels of VEGF expression in a nwnber ofhwnan rumor lines including
`
`25
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`glioblastoma multiforme. hemangioblastoma. other central nervous system neoplasms and AIDS(cid:173)
`
`associated Kaposi's sarcoma (Plate, K. et al. (1992) Nature 359: 845-848; Plate. K. et al. (1993)
`
`Cancer Res. 53: 5822-5827; Berkman, R. et al. (1993) J. Clin. Invest. 91: 153-159; Nakamura, S.
`
`et al. (1992) AIDS Weekly, 13 (I)). High levels of VEGF also have been reported in hypoxia
`
`induced angiogenesis (Shweiki, D. et al. ( 1992) Nature 359: 843-845).
`
`30
`
`VEGF mediates its biological effect through high aff mity VEGF receptors which are
`
`selectively expressed on endothelial cells during, for example. embryogenesis (Millauer, B., et al.
`
`( 1993) Cell 72: 835-846) and rumor formation. VEGF receptors typically are class Ill receptor(cid:173)
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`type tyrosine kinases characterized by having several, typically 5 or 7, immw10globulin-like loops
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`in their amino-terminal extracel!ular receptor ligand-binding domains (Kaipainen et al., J. Exp.
`
`Med. 178:2077-2088 (1993)). The other two regions include a transmembrane region and a
`
`carboxy-tenninal intracellular catalytic domain intenupted by an insertion of hydrophilic
`
`interkinase sequences of variable lengths, called the kinase insert domain (fennan et al.,
`
`5
`
`Oncogene 6: 1677-1683 (1991)). VEGF receptors include flt-I, sequenced by Shibuya M. et al.,
`
`Oncogene 5, 519-524 (1990); flk-1 , sequenced by Matthews W. et al. Proc. Natl. Acad. Sci. USA,
`88:9026-9030 (1991) and KDR the hwnan homologue offlk-1 , described in PCT/US92/01300,
`
`filed February 20, 1992, and in Terman et al., Oncogene 6: 1677-1683 (1991 ).
`
`High levels of flk-1 are expressed by endothelial cells that infiltrate gliomas (Plate, K. et
`
`10
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`al., (l 992) Nature 359: 845-848), and are specificaJJy upregulated by VEGF produced by human
`
`glioblastomas (Plate. K. et al. (l 993) Cancer Res. 53: 5822-5827). The finding of high levels of
`
`flk-1 expression in glioblastoma associated endothelial cells (GAEC) suggests that receptor
`
`activity is induced during twnor formation. since flk-l transcripts are barely detectable in normal
`
`brain endothelial cells. This upregulation is confined to the vascular endothelial cells in close
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`15
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`proximity to the tumor. Blocking VEGF activity with neutralizing anti-VEGF monoclonal
`
`antibodies (mAbs) results in inhibition of the growth of human tumor xenografts in nude mice
`
`(Kim. K. ct al. ( 1993) Nature 362: 841-844 ), suggesting a direct rt lie for VEGF in tumor-related
`
`Various chemotherapeutic drugs also have been shO\\TI to block functions of activated,
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`20
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`dividing endothelial cells critical to angiogenesis. or to kill such cells. Such collateral damaging
`
`effects on a genetically stable normal host cell. in addition to the chemotherapeutic agent's effect
`
`upon the tumor cells. contribute significantly to the in vivo anti-tumor efficacy of chemotherapy.
`
`However, the standard use of chemotherapeutic agents has obvious undesirable side-effects upon
`
`the normal cells of patients, limiting its use. Administration of chemotherapeutic agents in their
`
`25
`
`usual doses and at usual dosage frequencies are commonly associated with side-effects, including,
`
`but not limited to. myelosuppression. neurotoxicity. cardiotoxicity, alopecia, nausea and vomiting,
`
`nephrotoxicity, and gastrointestinal toxicity. Further, patients' tumors often also develop
`
`resistance to the chemotherapeutic agents after initial exposure to the drugs.
`
`A desirable method and composition for controlling angiogenesis should be well
`
`30
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`tolerated, have few or no side-effects, and prevent new vessel formation at sites of disease
`
`without interfering with required physiologic angiogenesis in normal sites. It should be
`
`effective and, in the case of neoplastic disease, overcome the problem of the development of
`
`drug resistance by tumor cells. In so doing, it should permit targeted therapy without the
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`accurate identification of all disease sites. The present invention addresses many of the
`
`problems with existing materials and methuds.
`
`5
`
`SUMMARY OF THE INVENTION
`
`The present invention provides a method of treating an angiogenic dependent
`
`condition in a mammal comprising administering an anti-angiogenic molecule and a
`
`chemotherapeutic agent to the mammal, in an amount and frequency effective, in
`
`combination, to produce a regression or arrest of the condition without significant toxicity
`
`I 0
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`from the chemotherapeutic agent. The angiogenic dependent condition may be selected from
`
`the group consisting of neoplasm, collagen-vascular disease or auto-immune disease.
`
`including a solid tumor neoplasm. including breast carcinoma. Jung carcinoma, prostate
`
`carcinoma. colon carcinoma. prostate carcinoma. ovarian carcinoma. neuroblastoma. central
`
`nervous system tumor, neuroblastoma, glioblastoma multiforme or melanoma. The mammal
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`15
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`receiving the treatment is preferably a human.
`
`The anti-angiogenic molecules inhibit the action of a vascular endothelium survival
`
`factor. which include receptors and their ligands. Vascular endothelium survival factors
`
`include :.\.'.. · ·
`
`~eluding angiogenic growth factors such as VEC •: r;!ceptor. including flk-
`
`1/KDR ~ccc!"tnr. •lr flt-4 receptor and VEGF. Examples of other \·ascular endothelial survival
`
`20
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`factors are imegnn avP;. avP3 ligand. Tie2/tek ligand. Tie2/tek. cndoglin ligand. endoglin.
`
`neuropilin ligand, neuropilin. thrombospondin ligand. thrombospondin, PDGFa. PDGFa
`
`receptor. PDGFp. PDGFP recepcor. aFGF. aFGF receptor. bFGF. bFGF receptor, TGFP,
`
`TGFP receptor, EGF, EGF receptor, angiostatin. angiostatin receptor, angiopoetin,
`
`angiopoeitin receptor. PLGF, PLGF receptor. VPF, or YPF receptor. Optionally, the ligand is
`
`25
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`selected from the group consisting of VEGF (VEGF-A). VEGF-B. VEGF-C. or VEGF-D.
`
`The anti-angiogenic molecule may be selected from the group consisting of antibody,
`
`antibody fragment. small molecule or peptide.
`
`Preferred embodiments of the present invention include antibodies selected from the
`
`group consisting of mouse antibody, rat antibody. chimeric antibody, humanized antibody or
`
`30
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`human antibody. A preferred antibody is IMC-IC! I.
`
`Preferably, IMC-IC! 1 is administered in a dose of from about 5 mg/m~ to about 700
`
`mg/m~ about daily to about every 7 days. more preferably a dose of from about 7.5 mg/m2 to
`
`about 225 mg/m~, about twice per week. Optionally. the IMC-IC 11 is administered at a dose
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`and frequency sufficient to substantially saturate the VEGF receptor. Optionally, the anti(cid:173)
`
`angiogenic molecule is administered in a dose and frequency sufficient to substantially
`
`saturate the target of the anti-angiogenic molecule. In another embodiment, the anti(cid:173)
`
`angiogenic molecule is administered in a dose equivalent to that ofIMC-lCl l, administered
`
`5
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`in a dose of from about 5 mg/m2 to about 700 mg/m2 about daily to about every 7 days, more
`
`preferably a dose of from about 7.5 mg/m2 to about 225 mg/m2, about twice per week.
`
`The chemotherapeutic agent may be selected from the group consisting of vinca
`
`alkaloid, camptothecan, taxane, or platinwn analogue, including vincristine, vinblastine,
`
`vinorelbine, vindesine, paclitaxel, docetaxel, 5 FU, cisplatin, carboplatin, iranotecan,
`
`10
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`topotecan or cyclophospbamide. The chemotherapeutic agent is administered in a low-dose
`
`regimen. Preferably the chemotherapeutic agent is administered at Jess than about 20% of the
`
`maximum tolerated dose, more preferably at less than about I 5% of the maximum tolerated
`
`dose, more preferably at less than about I 0% of the maximum tolerated dose, more preferably
`
`at less than about 5% of the maximum tolerated dose, and most preferably at less than about
`
`15
`
`2% of the maximum tolerated dose. In one embodiment of the invention the
`
`chemotherapeutic agent is administered at a dose intensity less than about 20% of the dose
`
`intensity of the chemotherapeutic agent when used in a conventional chem.·1l1erapeutic
`
`regimen, pre~·:r:!: ly :it - J .)se intensity less than about 10% of the dose i,te· .. :• of the
`
`chemotherapt!utic agent when used in a conventional chemotherapeutic reg!men, and more
`
`20
`
`preferably at a dost! intensity less than about 5% of the dose intensity of the chemotherapeutic
`
`agent when used in a conventional chemotherapeutic regimen.
`
`In one preferred embodiment the vinblastine is administered in a dose from about 0.5
`
`mg/m2 to about 3 mg/m2 from about once every 3 days to about once every 7 days. In another
`
`embodiment, the chemotherapeutic agent is administered in a dosage and frequency that is of
`
`25
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`substantially equivalent efficacy to vinblastine in a dose from about 0.5 mg/m2 to about 3
`
`mg/m2 from about once every 3 days to about once every 7 days. Optionally the
`
`chemotherapeutic agent is administered more frequently than about every three weeks, or
`
`more frequently than about every seven days.
`
`The present invention also includes a kit for treating an angiogenic dependent
`
`30
`
`condition in a mammal comprising the anti-angiogenic molecule and the chemotherapeutic
`
`agent, which are provided to be administered in an amount and frequency effective, in
`
`combination, to produce a regression or arrest of the condition while minimizing or
`
`preventing significant toxicity of the chemotherapeutic agent
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`BRIEF DESCRIPTION OF FIGURES
`
`Figure I is the encoding nucleotide sequence and deduced amino acid sequence ofVH
`
`and Vt domains ofIMC-lCl I (c-plCI I).
`
`5
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Throughout this application, various articles and patents, and patent application are
`
`referenced. Disclosures of all of these publications in their entireties are hereby incorporated
`
`10
`
`by reference into this application.
`
`The present invention comprises a method of treating or controlling an angiogenic
`
`dependent condition in a mammal. comprising administering an anti-angiogenic molecule and
`
`a chemotherapeutic agent in amounts and frequencies effective to produce, in combination. a
`
`regression or arrest of the angiogenic dependent condition, while minimizing or preventing
`
`15
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`significant toxicity.
`
`The benefits of the combination of an anti-angiogenic molecule and a
`
`chemotherapeutic agent of the present invention include an improvement in the :;catment and
`
`control of an angiogenic dependant condition with reduced doses of a chem,Hhl.' '.Oeutic agent
`
`administered at increased frequency, without significant toxicity. The combinati·Jn can be
`
`20
`
`administered for a prolonged period of time, or optionally a shorter duration o f treatment may
`
`be administered due to the increased effectiveness of the combination. Toxicity is reduced or
`
`eliminated without a loss of effectiveness. The administration of the treatment of the
`
`invention can overcome the problems of drug resistance that develops with standard
`
`chemotherapeutic regimens.
`
`25
`
`The anti-angiogenic molecule functions to inhibit or prevent angiogenesis, thereby
`
`treating or controlling the angiogenic dependent condition by inhibiting or blocking
`
`(antagonizing) the effect of vascular endothelial survival factors. These survival factors are
`
`receptors or their ligands, upon which vascular endothelium depends, either directly or
`
`30
`
`indirectly, for growth and/or survival. They play a role in allowing vascular endothelial cells
`
`to recovery from injury or insult, which, absent the effect of the survival factor would result
`
`in cell death or apoptosis. Survival factors include vascular endothelial cell growth factors or
`
`mitogens, as well as those factors which do not appear to have a direct growth-stimulatory
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`effect but allow the cells to n cover from injury.
`
`The survival factors tl,.at arf: receptors are located on vascular endothelial cells or
`
`optionally, may be located on other cell types including, but not limited to tumor cells. The
`
`anti-angiogenic molecule inhibit binding to, and/or activation of, receptors, inhibit their
`
`5
`
`expression, or inhibit the binding or expression of ligands.
`
`Examples of survival factors include VEGF receptors, including but not limited to flt-
`
`1 (VEGFRl), flk-1/KDR (VEGFR2), flt-4 (VEGFR3), their ligands VEGF, VEGF-B, VEGF(cid:173)
`
`C, and VEGF-D, integrin aVp3, Tie2/tek, endoglin (CD105), neuropilin, thrombospondin
`
`and their ligands, and PDGFa, PDGFP. aFGF, bFGF, and TGFp, as well as EGF, angiostatin,
`
`10
`
`and angiopoeitin, vascular penniability factor (VPF), and placenta-like growth factor (PLGF)
`
`and their receptors.
`
`Suitable types of anti-angiogenic molecules include, but are not limited to antibody,
`
`antibody fragment, small molecule or peptide. An antibody can be derived from any
`
`mammalian species. Optionally. the antibody is of mouse, rat, rabbit, or human origin.
`
`15
`
`Preferably the antibody is chimeric, more preferably the antibody is humanized, and even
`
`more preferably the antibody is human. Suitable antibody fragments include. for example,
`
`Fab fragment. Fab' fragment, F(ab')~ fragment, monovalent single chain antibody (scFv),
`
`and diabodies (DAB).
`
`Examples of suitable anti-angiogenic molecules that are antagonists to vascular
`
`20
`
`endothelium survival factors include. but are not limited to. VEGF receptor antagonist or
`
`VEGF antagonist, as disclosed in U.S. Patents Nos. 5,840,301, 5,861,499, 5,874,542,
`
`5,955,311, and 5,730,977, which are incorporated in their entirety by reference, aFGF
`
`receptor antagonist, aFGF antagonist, bFGF receptor antagonist, bFGF antagonist, PDGF
`
`receptor antagonist, PDGF antagonist. TGFP antagonist, Tie2/tek antagonist (P. Lin et al.,
`
`25
`
`Inhibition ofTwnor Angiogenesis Using a Soluble Receptor Establishes a Role for Tie2 in
`
`Pathologic Vascular Growth. J. Clin. Invest. 100(8) 2072 (1997)), endoglin (CD105)
`
`antagonist, as disclosed in U.S. Patents Nos 5,855,866, and 5,660,827, neuropilin antagonist,
`
`thrombospondin antagonist, and antagonists to the receptors for PDGFa, PDGFp, aFGF,
`
`bFGF, or TGFp, as well as antagonists to the receptors for EGF, angiostatin, angiopoeitin, or
`
`30
`
`VPF (Vascular Permeability Factor) as disclosed in U.S. Patents Nos. 5,036,003 and
`
`5,659,013. Also encompassed within the scope of the present invention are integrin receptor
`
`antagonists as disclosed in U.S. Patents Nos. 6,017,926, 6,017,925, 5,981,546, 5,952, 341,
`
`and 5,919, 792, integrin avP3 antagonists, as disclosed in U.S. Patents Nos. 5,780,426,
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`5,773,412, 5,767,071, 5,759,996, 5,753,230, 5,652,110, and 5,652,109, antagonists to
`
`placenta-like growth factor (PLGF) as disclosed in European Patent Application
`
`EP506477Al, thrombospondin antagonists as disclosed in U.S. Patent Nos. 5,840,692,
`
`5,770,563, 5,654,277, 5,648,461, 5,506,208, 5,399,667, 5,200,397, 5,192,744, and 5,190,918,
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`5
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`as well as those disclosed in U.S. Patents Nos. 5,965,132, 6,004,555 and 5,877,289, and PCT
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`Applications Nos. WO 99/16465, WO 97/05250, WO 98/33917. Also included are molecules
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`such as thalidomide, TNP-470, interferon-a (INF-a), and interleuk.in-12 (IL-12).
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`In many cases, the expression of a receptor and/or ligand is upregulated in an region
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`of angiogenesis. However, although located in an area of abnormal cells responsible for the
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`l 0
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`specific disease, exposed to high levels of ligand, and having upregulated receptors, the cells
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`of the vascular endothelium are largely normal and responsive to normal regulatory
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`mechanisms. Because the receptors exist on essentially normal endothelial cells, their
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`behavior is less likely to escape normal regulatory control. An advantage to blocking a
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`receptor, rather than its ligand, is that fewer anti-angiogenic molecules may be needed to
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`achieve such inhibition. as levels of receptor expression may be more constant than those of
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`the environmentally induced ligand. Although there are advantages to targeting receptors. it is
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`also possible. and within the scope of the present invention. to inhibit angiogenesis by
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`targeting the ligand for the receptor. either alone or in combination with blockade of the
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`receptor. Optionally. antagonism of the receptor is combined with antagonism of the ligand in
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`order to achieve even more efficient inhibition of angiogenesis.
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`A preferred embodiment of the invention is the combination of a chemotherapeutic
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`agent and a VEGF receptor antagonist. It has been shown that a major function of VEGF is to
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`promote the survival of endothelial cells comprising newly formed vessels (L. E. Benjamin,
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`et Al., Selective Ablation oflmmature Blood Vessels in Established Human Tumors Follows
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`25
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`Vascular Endothelial Growth Factor Withdrawal. J.Clin.Jnvest. I 03: 159-165 ( 1999), T. Alon,
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`et al., Vascular Endothelial Gro\.vth Factor Acts as a Survival Factor for Newly Formed
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`Retinal Vessels and Has Implications for Retinopathy of Prematurity. Narure Med. I: 1024-
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`1028 ( 1995), R.K. Jain, et al., Endothelial Cell Death, Angiogenesis, and Microvascular
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`Function after Castration in an Androgen-Dependent Tumor: Role of Vascular Endothelial
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`Growth Factor. Proc. Natl. Acad. Sci. U.S.A. 95:10820-10825 (1998)) Hence, the ability of
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`such cells to cope with the damage inflicted by continuous or frequent exposure to a
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`chemotherapeutic drug is selectively and significantly impaired when they are exposed to a
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`VEGF receptor antagonist, ( M. J. Prewett, et al., Antivascular Endothelial Growth Factor
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`Receptor (Fetal Liver Kinase 1) Monoclonal Antibody Inhibits Tumor Angiogenesis and
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`Growth of Several Mouse and Human Tumors. Cancer Res 59:5209-5218. (1999); T. A.
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`Fong, et al., SU5416 Is a Potent and Selective Inhibitor of the Vascular Endothelial Growth
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`Factor Receptor (Flk-1/kdr) That Inhibits Tyrosine Kinase Catalysis, Tumor Vasculariz.ation,
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`5
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`and Growth of Multiple Tumor Types. Cancer Res 59:99- I 06 ( 1999); N. Ferrara, et al.,
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`Clinical Applications of Angiogenic Growth Factors and Their Inhibitors. Nat.Med. 5:1359-
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`1364. ( 1999)). It is believed that the combination of continuous or frequent chemotherapy
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`with, for exarnpic:, interruption of the cell rescue mechanisms provided by activation of the
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`VEGF receptor plays a role in inducing vascular endothelial cell apoptosis.
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`In a preferred embodiment of the invention, the anti-angiogenic molecule is an
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`antagonist to VEGF or the VEGF receptor. While the expression of the VEGF receptor and
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`ligand is low in normal endothelial cells that are not in or near a region of angiogenesis,
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`VEGF receptors present on tumor infiltrating vascular endothelial cells are upregulated, as is
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`the expression of the VEGF ligand by tumor cells. Blocking the interaction between VEGF
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`and its receptors can inhibit angiogenesis. and thereby tumor growth, while not significantly
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`effecting normal endothelial cells at other sites, where vascular endothelial celJ receptors have
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`not been upregulated. In one embodiment of the present invention. antagonism of the VEGF
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`receptor is combined with antagonism of the VEGF ligand in order to achieve even more
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`efficient inhibition of angiogenesis. In other embodiments of the invention antagonists to one
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`20
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`or more than one of the VEGF receoptors or ligands are administered. VEGF (or VEGF-A) is
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`the ligand for VEGFRI and VEGFR2, VEGF-B is the ligand for VEGFR2, VEGF-C is the
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`ligand for VEGFR3, VEGFR4. and possibly VEGFR2. and VEGF-D is the ligand for
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`VEGFR2 and VEGFR3. Optionally, the effect of more than one form ofVEGF is inhibited.
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`An example of an antagonist to a VEGF receptor (flk-1) is the antibodies DC 101,
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`25
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`described in the Examples. Another is A.4.6.1 and its chimeric and humanized form as
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`disclosed in L. G. Presta, Humaniz.ation of an Anti-vascular Endothelial Growth Factor
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`Monoclonal Antibody for the Therapy of Solid Tumors and Other Disorders. Cancer
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`Research, 57, 4593-4599 (1997), which is hereby incorporated by reference. A preferred
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`VEGF antagonist is the mouse-human chimeric antibody IMC-1C11 which is a KOR
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`30
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`antagonist, and is disclosed in U.S. Application 09/240,736, which is hereby incorporated by
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`reference. The encoding nucleotide sequences and deduced amino acid sequences of the V H
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`and V L domains are shown in Figure l .
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`The chemotherapeutic agent of the present invention functions, in combination with
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`the anti-angiogenic molecule, to cause a cytotoxic effect on the vascular endothelial cells
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`involved in angiogenesis. A number of chemotherapeutic agents have been identified as
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`having anti-angiogenic activity and are suitable for use in the practice of the present
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`invention. Examples include, but are not limited to, taxanes, including but not limited to
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`5
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`paclitaxel and docetaxel, camptothecin analogues, including but not limited to iranotecan and
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`topotecan, platinum analogues including but not limited to cisplatin and carboplatin, 5FU,
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`and vinca alkaloids, including but not limited to vinblastine, vincristine, vindesine and
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`vinorelbine.
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`The present invention provides a low dose application of a chemotherapeutic agent
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`10
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`administered in combination with an anti-angiogenic molecule in an amount and frequency
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`that, in combination, provides effective therapy without significant side-effects. Effective
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`therapy is therapy that provides regression or arrest of the angiogenic dependant condition.
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`An effective amount of anti-angiogenic molecule and chemotherapeutic agent is an amount of
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`each, that in combination controls (causes regression or arrest) the condition being treated
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`without producing significant chemotherapy induced toxicity. The meaning of significant
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`toxicity is well known to one of ordinary skill in the art, and includes toxicities that
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`cumulatively or acutely effect a patient" s quality of life and/or limit the amount of
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`chemotherapeutic agent than can be administered.
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`Examples of chemotherapy induced t0xicity that can be minimized or prevented by
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`20
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`the present invention include, but are not limited to. myelosuppression, neurotoxicity,
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`cardiotoxicity, alopecia. nausea and vomiting, nephrotoxicity, and gastrointestinal toxicity.
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`The low dose administration of a chemotherapeutic agent without significant toxicity permits
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`prolonged treatment if desired. Additionally, the low dose manner of chemotherapy
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`administration in the present invention can overcome the problem of the development of
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`chemotherapeutic drug resistance by the patient's tumor cells that occurs with current
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`chemotherapeutic regimens which consist of higher doses of drug administered intenninently
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`with longer time intervals between treatment. The present invention delays, reduces, or even
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`circumvents the problem of acquired drug resistance by targeting the genetically stable
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`endothelial cells of newly formed tumor blood vessels, rather than genetically unstable tumor
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`30
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`cells which are prone to mutate and develop resistance. Encompassed within the scope of the
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`present invention is the administration of amounts of chemotherapy that are insufficient to
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`have a cytotoxic effect on tumor cells yet have anti-angiogenic properties as a result of the
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`drug's effect on vascular endothelial cells.
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`The low-dose adminisb ation of chemotherapeutic agents, to achieve therapeutic
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`effects without significant toxicity (side effects) is readily po