PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of mabsLink to Publisher's site
 
MAbs. 2009 May-Jun; 1(3): 247–253.
PMCID: PMC2726597

Antibody drug-conjugates targeting the tumor vasculature

Current and future developments

Abstract

Reducing the blood supply of tumors is one modality to combat cancer. Monoclonal antibodies are now established as a key therapeutic approach for a range of diseases. Owing to the ability of antibodies to selectively target endothelial cells within the tumor vasculature, vascular targeting programs have become a mainstay in oncology drug development. However, the antitumor activity of single agent administration of conventional anti-angiogenic compounds is limited and the improvements in patient survival are most prominent in combinations with chemotherapy. Furthermore, prolonged treatment with conventional anti-angiogenic drugs is associated with toxicity and drug resistance. These circumstances provide a strong rationale for novel approaches to enhance the efficacy of mAbs targeting tumor vasculature such as antibody-drug conjugates (ADCs). Here, we review trends in the development of ADCs targeting tumor vasculature with the aim of informing future research and development of this class of therapeutics.

Key words: tumor, vasculature, immunotherapy, antibody-drug conjugates, monoclonal antibody, cancer, angiogenesis

Therapeutic Antibodies and Antibody-Drug Conjugates for Cancer Therapy

Antibody-based therapeutics are of growing significance for cancer therapy as evidenced by twelve such drugs approved for oncologic indications since 1995, including nine in the USA.1 Among them, eight had more than US $1 billion global market revenues and the combined global revenues exceed US $50 billion. Currently, there are 121 oncology monoclonal antibodies (mAbs) in clinical development. Over the last six years, the success rates for approval of antibody therapeutics entering clinical development was 17%, which makes them an attractive class of therapeutics for oncology drug development.2,3 Despite the success of therapeutic mAbs in the clinic, naked antibodies targeting cell surface tumor antigens expressed on carcinomas are rarely curative by themselves, and most are administered in combination with chemotherapy.4 Similarly, antiangiogenic drugs when administered as single agents induced only limited therapeutic benefit in the clinic and were most successful when administered in combination with chemotherapy.5 These limitations spurred the development of a variety of technologies aimed at the enhancement of mAb therapeutics. Recent advances in antibody drug conjugate technology (ADC) allow for the combination of the selectivity of mAbs with the potency of cytotoxic drugs with the goal to reduce systemic toxicity and to increase efficacy and the therapeutic benefit to carcinoma patients.

ADCs consist of an antibody conjugated to a cytotoxic drug via a linker. The therapeutic concept of ADCs is to use an antibody as a vehicle to deliver a cytotoxic drug selectively to the tumor tissue by targeting an antigen expressed on the surface of a malignant cell. ADCs are prodrugs that require drug release for activation, which occurs commonly after ADC internalization into the target cell, providing greatly improved tumor-to-normal tissue ratios of ADC drugs compared to systemic chemotherapy. Numerous pre-clinical efficacy studies have shown that ADCs enhance the antitumor activity of “naked” antibodies and reduce the systemic toxicity of the cytotoxic drugs conjugated to the antibody.6,7

Important parameters for ADC development include the selection of the target antigen, the kinetics and efficacy of conjugate internalization by the tumor cells, the drug potency and the stability of the linker between drug and antibody (reviewed in ref. 8). Other parameters reported to be important include the drug/antibody ratios912 and the methods used for drug conjugation and their effects on the pharmacodynamic properties of the ADCs.13

During the development of ADCs, it became apparent that molecular mechanisms regulating drug linker cleavage, enabling the release of active drug, remained only partially understood. Certain changes in the linker chemistry and drug conjugation methods resulted in alterations in the pharmacodynamic and safety characteristics of different drug linker types tested.912 The nature and magnitude of the biological consequences of these changes in the drug linker chemistry are difficult to predict based on the biological models currently available, and thus certain aspects of drug linker engineering remain rather empirical in nature.

Despite these changes in the development of ADC technology, clinical validation of the ADC concept has been provided earlier by gemtuzumab ozogamicin, a humanized anti-CD33 antibody conjugated to the tubulin binding agent, calicheamicin, which is approved in the USA for the treatment of acute myeloid leukemia (AML).14 Two recent cases of ADCs in the clinic were shown to induce unusually high objective response rates in early clinical studies: SGN-35 in Hodgkins lymphoma induced 54% objective response rates (ORR) when administered at doses of ≥1.2 mg/kg.15 Secondly, trastuzumab-DM1 induced 44% ORRs in breast carcinoma when administered at 3.6 mg/kg. These results from phase I and II clinical studies, respectively, provided clinical evidence for the extraordinary potential of these classes of compounds, with the corresponding naked antibody being only minimally active in the same indications.

Four Main Classes of Drug-Linker Compounds Currently Being Developed in the Clinic

Upon binding to cell surface antigens, many mAbs internalize through a process known as receptor mediated endocytosis into lysosomes. The lysosomal compartment is both acidic (pH 5) and rich in proteolytic enzymes (reviewed in ref. 16). The first and most advanced class of drug linker compounds employed for ADCs (doxorubicin, calicheamicin) consist of acid-labile hydrazone linkers, which are cleaved within the intracellular compartment of lysosomes as a consequence of the lower pH within this compartment compared to the systemic circulation (reviewed in ref. 4).9,11,17 The second class of drug linker compounds undergoing clinical testing are disulfide based. Disulfide linkers are selectively cleaved in the cytosol due the more reductive intracellular environment compared to the extra cellular milieu.9,11,18 A third class of “non-cleavable,” thioether linkers was developed more recently. The release of free, active drug by this class of drug linker compounds is realized by catabolic degradation of internalized antibodies in the lysosomal compartment, releasing drug cleavage products that function as the active, cytotoxic drug component.1820 Finally, a fourth class, peptide linkers, with the potential for selective cleavage within the lysosomal compartment by lysosomal proteases such as cathepsin-B, was developed.17,20,21 Peptide linkers are associated with increased serum stability of ADCs and improved anti-tumor effects compared to hydrazone linker compounds.

Biological Rationale to Develop Vascular Targeting ADCs (VT-ADCs)

The prerequisite for the success of the anti-angiogenic strategy is the identification of pathophysiological differences between endothelial cells within tumor and normal tissue vessels that can be harnessed therapeutically. A variety of biological and physiological differences between normal and tumor vasculature have been described, including the constant remodeling of tumor vessels, their reliance on a tubulin cytoskeletal network for functional integrity, a lack of associated pericyte cells and the increased vascular permeability of tumor vasculature.2226

A growing body of experimental data also demonstrates significant differences in the expression of genes or splice forms between tumor and normal vasculature (reviewed in refs. 25 and 27), providing unique therapeutic targets for vascular targeting. More recently, gene expression profiling and proteomic mapping studies conducted with endothelial cells isolated from the vasculature of experimental models or patient derived tumors led to the identification of distinct molecular signatures within endothelial cells of the tumor vasculature. Several of the genes identified are currently being considered as putative targets for vascular targeting approaches (Table 1).2833 In addition, the internalization and turnover rates of several membrane associated genes were found to be increased on endothelial cells located within tumors or when grown in culture simulating tumor like conditions.34 Importantly, significant differences in the proteolytic environment and changes in the composition of the extra-cellular matrix within the tumor vasculature were identified.34,35 Endothelial cells within the tumor vasculature proliferate at much higher rates compared to normal, quiescent vasculature.36,37 In support of this notion, small molecule compounds targeting the tubulin structures were shown to be efficacious vascular targeting agents. Among the most promising tubulin binding agents are derivatives of combretastatins, colchicines and dolastatin 10.38 In summary, the magnitude and the variety of the molecular and cellular changes between the endothelium in tumors versus normal tissues provide a wealth of opportunities for the development of vascular targeting agents (VTAs) that are designed to deliver a therapeutic agent selectively to the tumor vasculature, in particular, VT-ADCs that leverage these biological differences (reviewed in ref. 39).

Table 1
Promising, internalizing cell surface antigens overexpressed on human tumor vasculature for ADC development

Potential Advantages of VT-ADCs for Drug Development

The recent FDA approvals of therapeutic compounds interfering with VEGF induced angiogenesis for the treatment of solid tumors has validated the anti-angiogenic approach as a viable therapeutic strategy for the treatment of solid tumors.40 Given this clinical success, the focus of future clinical and preclinical oncology research is likely to include vascular targeting strategies. Importantly, VT-ADCs are not associated with some of the limitations of “naked” antibodies targeting antigens expressed on the tumor cells. For example, therapeutic antibodies and ADCs are known to permeate tumors inefficiently. Typically, only 0.001–0.01% of the injected antibody localizes to tumors in humans.41 Endothelial cells usually constitute the first cell layer encountered by therapeutics administered intravenously. Because the vascular endothelial cells are in direct contact with the circulating blood, the serum levels of vascular targeting agents represent the on-target drug exposure levels, and limited tumor perfusion does not affect target exposure.42,43 Such favorable exposure/efficacy relationship of vascular targeting agents may provide an important advantage for drug development by potentially reducing the exposure/efficacy ratio and undesired on- and/or off-target toxicities. Furthermore, the vascular targeting approach should be applicable to most solid tumor types, based on their common dependence on angiogenesis for growth.44 Furthermore, thousands of tumor cells rely on each capillary for oxygen and nutrients supplies, and even limited damage to the tumor vasculature is likely to produce multiple tumor cell deaths.45 Importantly, endothelial cells are less likely to undergo somatic mutations and therefore are less prone to develop drug resistance, a common feature of prolonged treatment of carcinomas with drugs targeting neoplastic cells.46 However, evidence from preclinical studies suggests that endothelial cells within tumors can acquire changes in the genome via uptake of tumor cell DNA, and thus may be prone to develop resistance towards anti-angiogenic therapy.47 Finally, there is potential for synergism between cytotoxic compounds targeting neoplastic tumor cells within the tumor and vascular targeting compounds. In support of this notion, several VTAs, when combined with other anti-neoplastic agents, induced improved therapeutic effects in preclinical models.48

Development of VTAs

VTAs induce anti-tumor effects via rapid and selective destruction of blood vessels within established tumors, leading to a collapse in tumor blood flow and tumor cell death due to ischemia and extensive hemorrhagic necrosis. Low molecular weight VTAs are also known as vascular disrupting agents (VDAs).49 VTAs can be broadly divided into two classes, low-molecular-weight compounds and ligand-directed macromolecules such as monoclonal antibodies (reviewed in ref. 27). Small molecule VTAs exploit pathophysiological differences between endothelial cells present in tumor and normal tissues to achieve selective targeting of tumor vessels. The clinical data generated with different types of VTAs demonstrated their ability to effectively interfere with tumor angiogenesis. However, the dose levels required to achieve anti-angiogenic responses were frequently close to the maximal tolerated dose (MTD), suggesting a narrow therapeutic window (reviewed in refs. 27 and 50).

The clinically most advanced class of small-molecular-weight compounds targeting tumor vasculature are flavonoids (FAAs). Among the FAAs, LM985 and DMXAA were developed in early stage clinical trials (Table 2).51,52 Several tubulin binding agents such as colchicines, vincristine, vinblastine, auristatins and combretastatins were shown to destabilize the tubulin cytoskeleton and to induce disruption of the tumor vasculature.48 Among these tubulin binding agents, several were tested in clinical studies, including AVE8062A (Combretastatin A-4 prodrug, formerly AC-7700), Oxi4503 (Combretastatin A-1 disodium phosphate), ZD6126 (Phosphate prodrug of N-acetylcolcholin), ABT-751 (Sulfonamide, binding to β-tubulin), TZT-1027 (Synthetic derivative of dolastatin 10, formerly known as Auristatin-PE) (Table 2). In general, VTAs induce vascular damage and a reduction in tumor blood perfusion. Therefore, it will be interesting to test the potential of VTAs as ADCs in conjunction with vascular targeting compounds, and to study their ability to interfere with tumor angiogenesis and to block tumor growth.

Table 2
Cytotoxic agents with anti-angiogenic activities

Despite the clinical successes of therapeutic antibodies in oncology and the remarkable potency of cytotoxic compounds targeting tumor vasculature, only limited efforts were directed in the past towards the investigation of the effects of ADCs targeting tumor vascular antigens. The reasons for the absence of such research activities are unclear. However, the most plausible explanation is that in most cases, hybridoma derived antibodies generated in mice immunized with human antigens failed to cross react with the murine orthologs. While these circumstances allowed for efficacy studies of antibodies targeting tumor antigens in mice implanted with human tumors, it precluded testing for vascular targeting purposes in rodents, because the tumor vasculature is host derived, and therefore is not recognized by the vast majority of therapeutic antibodies. However, recent technology improvements in antibody engineering, including phage display technologies, helped to overcome these initial limitations and enabled the generation of cross-species-reactive compounds. The key advantage of cross-species-reactive antibodies for vascular targeting purposes is that efficacy experiments also provide information regarding safety aspects, ultimately defining their therapeutic index. It is important for lead selection of ADCs that the therapeutic index information is available, and can be included for decision making in drug development.

Given these circumstances, it is not surprising that only a handful of immunotherapeutics conjugated to cytotoxic drugs (ADCs) or fused to cytokines (cytokine fusion chimeras) were developed in the clinic. The two most advanced clinical programs employ monoclonal antibodies targeting tumor specific splice forms of fibronectin and tenascin. L19 is a monocolonal antibody interacting specifically with an EDB-containing splice form of fibronectin, which is selectively expressed on the tumor vasculature within a variety of solid tumors. Several therapeutic derivatives of the L19 antibody were generated and shown to be efficacious when tested in preclinical models,25 and data from early clinical trials demonstrated tumor vasculature specific activities.

Tenascins comprise a family of four extracelllular matrix glycoproteins that are widely expressed in different types of connective tissues. Detailed immunohistochemical analysis revealed that the C-terminal domain of tenascin-C is overexpressed in aggressive brain tumors and some lung tumors, with a prominent perivascular staining pattern.53 Two high affinity human antibodies, G11 and F16, were shown to bind to tumor vascular specific isoforms and to induce anti-tumor effects in preclinical models of human carcinomas.54,55

Prostate specific stem cell antigen (PSMA) is a membrane glycoprotein that is predominantly expressed in the prostate, and serum concentrations are often increased in patients with prostate cancer.56 Several studies reported overexpression of PSMA in the neovasculature of different solid tumors in cancer patients.57 The anti-PSMA antibody huJ591 was conjugated to various toxins and radionucleotides and is currently being tested for therapeutic applications in prostate cancer and several solid tumor indications.58

The recent technology improvements in antibody engineering, including the phage display technologies, will help to overcome the initial limitations of first generation, mouse hybridoma-derived antibodies which were selective for human antigens. The availability of novel platforms allowing the generation of cross species reactive targeting vehicles will enable the generation of novel, species cross-reactive VT-ADCs, representing an essential tool for the development of ADC with optimized drug-linker properties for vascular targeting purposes.

Future Perspectives

VT-ADCs circumvent many of the limitations encountered when developing immunotherapeutics targeting antigens on neoplastic tumor cells (Table 3). In addition, major pathophysiological changes at the molecular and cellular level between the endothelium associated with tumors versus normal host tissues have been identified and provide an enormous opportunity to target tumor vasculature selectively. The development of VT-ADCs is particularly promising, as they harness several aspects of tumor vasculature, including the high proliferation rates of endothelial cells. However, the development of ADCs in oncology takes longer, is more complex and is less well defined than for naked antibodies. Two conceptually different approaches can be considered for the selection of novel drug linker compounds with utility for vascular targeting. The first strategy takes into account the empirical nature of successful drug linker design for ADCs in oncology and is based on the random screening of chemical libraries to identify drug linkers with optimal properties for vascular targeting purposes. An alternative effort is based on the principles of rational drug design, taking advantage of the rapidly increasing knowledge of the pathophysiological changes between normal and tumor vasculature, such as provided by recent studies employing proteomic and genomic approaches. The rational drug-linker design approach may also include identification of novel peptide linkers that are cleaved selectively by proteases found to be upregulated predominantly on the tumor vasculature and/or on proliferating, activated endothelial cells. Alternatively, an avenue towards the delivery of drugs to endothelial cells may be represented by the targeted delivery of drugs to the vicinity of blood vessels, including the subendothelial extracellular matrix (ECM), followed by hydrolytic release of the drug. The recent advances determining the changes in gene expression within tumor vasculature combined with the new technologies enabling cross species reactive targeting vehicles and the recent improvements in drug linker technology provide the basis for continuous development of novel VT-ADCs with improved activities in patients with solid tumors.

Table 3
Vascular targeting ADCs (VT-ADCs) circumvent many of the limitations encountered when developing immunotherapeutics targeting antigens on neoplastic tumor cells

Acknowledgements

H-P.G., P.D.S. and I.S.G. are paid employees of Seattle Genetics, Inc. and are receiving salary and other compensation from the company.

Abbreviations

ADC
antibody-drug conjugate
AML
acute myeloid leukemia
FAAs
flavonoid
mAbs
monoclonal antibodies
ORR
objective response rate
PSMA
prostate specific stem cell antigen
VTA
vascular targeting agents
VT-ADC
vascular targeting ADC

Footnotes

Previously published online as a mAbs E-publication: http://www.landesbioscience.com/journals/mabs/article/8515

References

1. Reichert JM, Valge-Archer VE. Development trends for monoclonal antibody cancer therapeutics. Nat Rev Drug Discov. 2007;6:349–356. [PubMed]
2. Reichert JM. Monoclonal antibodies as innovative therapeutics. Curr Pharm Biotechnol. 2008;9:423–430. [PubMed]
3. Reichert JM, Wenger JB. Development trends for new cancer therapeutics and vaccines. Drug Discov Today. 2008;13:30–37. [PubMed]
4. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154–169. [PubMed]
5. Ma J, Waxman DJ. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Cancer Ther. 2008;7:3670–3684. [PMC free article] [PubMed]
6. Lambert JM. Drug-conjugated monoclonal antibodies for the treatment of cancer. Curr Opin Pharmacol. 2005;5:543–549. [PubMed]
7. Schrama D, Reisfeld RA, Becker JC. Antibody targeted drugs as cancer therapeutics. Nat Rev Drug Discov. 2006;5:147–159. [PubMed]
8. Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol. 2006;6:343–357. [PubMed]
9. Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66:4426–4433. [PubMed]
10. Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10:7063–7070. [PubMed]
11. Kovtun YV, Audette CA, Ye Y, Xie H, Ruberti MF, Phinney SJ, et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 2006;66:3214–3221. [PubMed]
12. Oflazoglu E, Stone IJ, Gordon K, Wood CG, Repasky EA, Grewal IS, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171–6180. [PubMed]
13. Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925–932. [PubMed]
14. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7:1490–1496. [PubMed]
15. Younes A, Forero-Torres A, Bartlett NL, Leonard JP, Lynch C, Kennedy DA, et al. Multiple complete responses in a phase 1 dose-escalation study of the antibody-drug conjugate SGN-35 in patients with relapsed or refractory CD30 positive lymphomas. Blood. 2008;112:1006. (ASH meeting abstract)
16. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137–1146. [PubMed]
17. Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21:778–784. [PubMed]
18. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–9290. [PubMed]
19. Alley SC, Zhang X, Okeley NM, et al. Effects of linker chemistry on tumor targeting by anti-CD70 antibody-drug conjugates. Proceedings of the AACR. 2007:48.
20. Doronina SO, Mendelsohn BA, Bovee TD, Cerveny CG, Alley SC, Meyer DL, et al. Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem. 2006;17:114–124. [PubMed]
21. Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102:1458–1465. [PubMed]
22. Darland DC, D'Amore PA. Blood vessel maturation: vascular development comes of age. J Clin Invest. 1999;103:157–158. [PMC free article] [PubMed]
23. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:685–693. [PubMed]
24. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62. [PubMed]
25. Neri D, Bicknell R. Tumour vascular targeting. Nat Rev Cancer. 2005;5:436–446. [PubMed]
26. Pluda JM. Tumor-associated angiogenesis: mechanisms, clinical implications and therapeutic strategies. Semin Oncol. 1997;24:203–218. [PubMed]
27. Thorpe PE, Chaplin DJ, Blakey DC. The first international conference on vascular targeting: meeting overview. Cancer Res. 2003;63:1144–1147. [PubMed]
28. Buckanovich RJ, Sasaroli D, O'Brien-Jenkins A, Botbyl J, Conejo-Garcia JR, Benencia F, et al. Use of immuno-LCM to identify the in situ expression profile of cellular constituents of the tumor microenvironment. Cancer Biol Ther. 2006;5:635–642. [PubMed]
29. Mittal V, Nolan DJ. Genomics and proteomics approaches in understanding tumor angiogenesis. Expert Rev Mol Diagn. 2007;7:133–147. [PubMed]
30. Pen A, Moreno MJ, Martin J, Stanimirovic DB. Molecular markers of extracellular matrix remodeling in glioblastoma vessels: microarray study of laser-captured glioblastoma vessels. Glia. 2007;55:559–572. [PubMed]
31. Peters BA, St Croix B, Sjöblom T, Cummins JM, Silliman N, Ptak J, et al. Large-scale identification of novel transcripts in the human genome. Genome Res. 2007;17:287–292. [PubMed]
32. Seaman S, Stevens J, Yang MY, Logsdon D, Graff-Cherry C, St Croix B. Genes that distinguish physiological and pathological angiogenesis. Cancer Cell. 2007;11:539–554. [PMC free article] [PubMed]
33. St Croix B, Rago C, Velculescu V, et al. Genes expressed in human tumor endothelium. Science. 2000;289:1197–1202. [PubMed]
34. Lampugnani MG, Orsenigo F, Gagliani MC, Tacchetti C, Dejana E. Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments. J Cell Biol. 2006;174:593–604. [PMC free article] [PubMed]
35. Albig AR, Roy TG, Becenti DJ, Schiemann WP. Transcriptome analysis of endothelial cell gene expression induced by growth on matrigel matrices: identification and characterization of MAGP-2 and lumican as novel regulators of angiogenesis. Angiogenesis. 2007;10:197–216. [PubMed]
36. Denekamp J. Endothelial cell proliferation as a novel approach to targeting tumour therapy. Br J Cancer. 1982;45:136–139. [PMC free article] [PubMed]
37. Denekamp J, Hobson B. Endothelial-cell proliferation in experimental tumours. Br J Cancer. 1982;46:711–720. [PMC free article] [PubMed]
38. Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer. 2005;5:423–435. [PubMed]
39. Burrows FJ, Thorpe PE. Vascular targeting—a new approach to the therapy of solid tumors. Pharmacol Ther. 1994;64:155–174. [PubMed]
40. Ferrara N, Mass RD, Campa C, Kim R. Targeting VEGF-A to treat cancer and agerelated macular degeneration. Annu Rev Med. 2007;58:491–504. [PubMed]
41. Epenetos AA, Snook D, Durbin H, Johnson PM, Taylor-Papadimitriou J. Limitations of radiolabeled monoclonal antibodies for localization of human neoplasms. Cancer Res. 1986;46:3183–3191. [PubMed]
42. Burrows FJ, Thorpe PE. Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature. Proc Natl Acad Sci USA. 1993;90:8996–9000. [PubMed]
43. Huang X, Molema G, King S, Watkins L, Edgington TS, Thorpe PE. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science. 1997;275:547–550. [PubMed]
44. Folkman J. Tumor angiogenesis. Adv Cancer Res. 1985;43:175–203. [PubMed]
45. Denekamp J. Vascular attack as a therapeutic strategy for cancer. Cancer Metastasis Rev. 1990;9:267–282. [PubMed]
46. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–676. [PubMed]
47. Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC, et al. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res. 2004;64:8249–8255. [PubMed]
48. Horsman MR, Siemann DW. Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies. Cancer Res. 2006;66:11520–11539. [PubMed]
49. Chaplin DJ, Horsman MR, Siemann DW. Current development status of small-molecule vascular disrupting agents. Curr Opin Investig Drugs. 2006;7:522–528. [PubMed]
50. Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004;10:415–427. [PubMed]
51. Jameson MB, Thompson PI, Baguley BC, Evans BD, Harvey VJ, Porter DJ, et al. Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent. Br J Cancer. 2003;88:1844–1850. [PMC free article] [PubMed]
52. Kerr DJ, Kaye SB, Cassidy J, Bradley C, Rankin EM, Adams L, et al. Phase I and pharmacokinetic study of flavone acetic acid. Cancer Res. 1987;47:6776–6781. [PubMed]
53. Carnemolla B, Castellani P, Ponassi M, Borsi L, Urbini S, Nicolo G, et al. Identification of a glioblastoma-associated tenascin-C isoform by a high affinity recombinant antibody. Am J Pathol. 1999;154:1345–1352. [PubMed]
54. Brack SS, Silacci M, Birchler M, Neri D. Tumor-targeting properties of novel antibodies specific to the large isoform of tenascin-C. Clin Cancer Res. 2006;12:3200–3208. [PubMed]
55. Silverman KJ, Lund DP, Zetter BR, Lainey LL, Shahood JA, Freiman DG, et al. Angiogenic activity of adipose tissue. Biochem Biophys Res Commun. 1988;153:347–352. [PubMed]
56. Bostwick DG, Grignon DJ, Hammond ME, Amin MB, Cohen M, Crawford D, et al. Prognostic factors in prostate cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124:995–1000. [PubMed]
57. Liu H, Moy P, Kim S, Xia Y, Rajasekaran A, Navarro V, et al. Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium. Cancer Res. 1997;57:3629–3634. [PubMed]
58. Milowsky MI, Nanus DM, Kostakoglu L, Sheehan CE, Vallabhajosula S, Goldsmith SJ, et al. Vascular targeted therapy with anti-prostate-specific membrane antigen monoclonal antibody J591 in advanced solid tumors. J Clin Oncol. 2007;25:540–547. [PubMed]
59. Cai W, Chen X. Anti-angiogenic cancer therapy based on integrin alphavbeta3 antagonism. Anticancer Agents Med Chem. 2006;6:407–428. [PubMed]
60. Max R, Gerritsen RR, Nooijen PT, Goodman SL, Sutter A, Keilholz U, et al. Immunohistochemical analysis of integrin alphavbeta3 expression on tumor-associated vessels of human carcinomas. Int J Cancer. 1997;71:320–324. [PubMed]
61. Ruegg C, Dormond O, Mariotti A. Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis. Biochim Biophys Acta. 2004;1654:51–67. [PubMed]
62. Oh P, Li Y, Yu J, Durr E, Krasinska KM, Carver LA, et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature. 2004;429:629–635. [PubMed]
63. Christian S, Pilch J, Akerman ME, Porkka K, Laakkonen P, Ruoslahti E. Nucleolin expressed at the cell surface is a marker of endothelial cells in angiogenic blood vessels. J Cell Biol. 2003;163:871–878. [PMC free article] [PubMed]
64. Huang Y, Shi H, Zhou H, Song X, Yuan S, Luo Y. The angiogenic function of nucleolin is mediated by vascular endothelial growth factor and nonmuscle myosin. Blood. 2006;107:3564–3571. [PubMed]
65. Feuerhake F, Füchsl G, Bals R, Welsch U. Expression of inducible cell adhesion molecules in the normal human lung: immunohistochemical study of their distribution in pulmonary blood vessels. Histochem Cell Biol. 1998;110:387–394. [PubMed]
66. Hemmerlein B, Scherbening J, Kugler A, Radzun HJ. Expression of VCAM-1, ICAM-1, E- and P-selectin and tumour-associated macrophages in renal cell carcinoma. Histopathology. 2000;37:78–83. [PubMed]
67. Kelly KA, Allport JR, Yu AM, Sinh S, Sage EH, Gerszten RE, et al. SPARC is a VCAM-1 counter-ligand that mediates leukocyte transmigration. J Leukoc Biol. 2007;81:748–756. [PubMed]
68. Chang SS, Gaudin PB, Reuter VE, O'Keefe DS, Bacich DJ, Heston WD. Prostate-specific membrane antigen: Much more than a prostate cancer marker. Mol Urol. 1999;3:313–320. [PubMed]
69. Huang X, Bennett M, Thorpe PE. Anti-tumor effects and lack of side effects in mice of an immunotoxin directed against human and mouse prostate-specific membrane antigen. Prostate. 2004;61:1–11. [PubMed]
70. Balza E, Castellani P, Zijlstra A, Neri D, Zardi L, Siri A. Lack of specificity of endoglin expression for tumor blood vessels. Int J Cancer. 2001;94:579–585. [PubMed]
71. Burrows FJ, Derbyshire EJ, Tazzari PL, Amlot P, Gazdar AF, King SW, et al. Upregulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin Cancer Res. 1995;1:1623–1634. [PubMed]
72. Matsubara S, Bourdeau A, terBrugge KG, Wallace C, Letarte M, et al. Analysis of endoglin expression in normal brain tissue and in cerebral arteriovenous malformations. Stroke. 2000;31:2653–2660. [PubMed]
73. Huminiecki L, Gorn M, Suchting S, Poulsom R, Bicknell R. Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis. Genomics. 2002;79:547–552. [PubMed]
74. Park KW, Morrison CM, Sorensen LK, Jones CA, Rao Y, Chien CB, et al. Robo4 is a vascular-specific receptor that inhibits endothelial migration. Dev Biol. 2003;261:251–267. [PubMed]
75. Seth P, Lin Y, Hanai J, Shivalingappa V, Duyao MP, Sukhatme VP. Magic roundabout, a tumor endothelial marker: expression and signaling. Biochem Biophys Res Commun. 2005;332:533–541. [PubMed]
76. Curnis F, Arrigoni G, Sacchi A, Fischetti L, Arap W, Pasqualini R, et al. Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia and myeloid cells. Cancer Res. 2002;62:867–874. [PubMed]
77. Lauret E, Catelain C, Titeux M, Poirault S, Dando JS, Dorsch M, et al. Membrane-bound delta-4 notch ligand reduces the proliferative activity of primitive human hematopoietic CD34+CD38low cells while maintaining their LTC-IC potential. Leukemia. 2004;18:788–797. [PubMed]
78. Patel NS, Dobbie MS, Rochester M, Steers G, Poulsom R, Le Monnier K, et al. Upregulation of endothelial delta-like 4 expression correlates with vessel maturation in bladder cancer. Clin Cancer Res. 2006;12:4836–4844. [PubMed]
79. Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL. Upregulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res. 2005;65:8690–8697. [PubMed]
80. Ran S, Huang X, Downes A, Thorpe PE. Evaluation of novel antimouse VEGFR-2 antibodies as potential antiangiogenic or vascular targeting agents for tumor therapy. Neoplasia. 2003;5:297–307. [PMC free article] [PubMed]
81. Witmer AN, Dai J, Weich HA, Vrensen GF, Schlingemann RO. Expression of vascular endothelial growth factor receptors 1, 2 and 3 in quiescent endothelia. J Histochem Cytochem. 2002;50:767–777. [PubMed]
82. Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol. 2004;14:171–179. [PubMed]
83. Rempel SA, Dudas S, Ge S, Gutiérrez JA. Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res. 2000;6:102–111. [PubMed]
84. Scheurer SB, Rybak JN, Rösli C, Neri D, Elia G. Modulation of gene expression by hypoxia in human umbilical cord vein endothelial cells: A transcriptomic and proteomic study. Proteomics. 2004;4:1737–1760. [PubMed]
85. Fathers KE, Stone CM, Minhas K, Marriott JJ, Greenwood JD, Dumont DJ, et al. Heterogeneity of Tie2 expression in tumor microcirculation: influence of cancer type, implantation site and response to therapy. Am J Pathol. 2005;167:1753–1762. [PubMed]
86. Moon WS, Park HS, Yu KH, Jang KY, Kang MJ, Park H, et al. Expression of angiopoietin 1, 2 and their common receptor Tie2 in human gastric carcinoma: implication for angiogenesis. J Korean Med Sci. 2006;21:272–278. [PMC free article] [PubMed]
87. Peters KG, Coogan A, Berry D, Marks J, Iglehart JD, Kontos CD, et al. Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis. Br J Cancer. 1998;77:51–56. [PMC free article] [PubMed]
88. Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS, Peters KG. Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res. 1997;81:567–574. [PubMed]
89. Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, et al. B7-H3 and B7-H4 expression in non-small-cell lung cancer. Lung Cancer. 2006;53:143–151. [PubMed]
90. Wu CP, Jiang JT, Tan M, Zhu YB, Ji M, Xu KF, et al. Relationship between co-stimulatory molecule B7-H3 expression and gastric carcinoma histology and prognosis. World J Gastroenterol. 2006;12:457–459. [PMC free article] [PubMed]
91. Hori K, Furumoto S, Kubota K. Tumor blood flow interruption after radiotherapy strongly inhibits tumor regrowth. Cancer Sci. 2008;99:1485–1491. [PubMed]
92. Kim TJ, Ravoori M, Landen CN, Kamat AA, Han LY, Lu C, et al. Antitumor and antivascular effects of AVE8062 in ovarian carcinoma. Cancer Res. 2007;67:9337–9345. [PubMed]
93. Chan LS, Malcontenti-Wilson C, Muralidharan V, Christophi C. Effect of vascular targeting agent Oxi4503 on tumor cell kinetics in a mouse model of colorectal liver metastasis. Anticancer Res. 2007;27:2317–2323. [PubMed]
94. Chan LS, Malcontenti-Wilson C, Muralidharan V, Christophi C. Alterations in vascular architecture and permeability following OXi4503 treatment. Anticancer Drugs. 2008;19:17–22. [PubMed]
95. LoRusso PM, Gadgeel SM, Wozniak A, Barge AJ, Jones HK, DelProposto ZS, et al. Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors. Invest New Drugs. 2008;26:159–167. [PubMed]
96. Raben D, Bianco C, Damiano V, Bianco R, Melisi D, Mignogna C, et al. Antitumor activity of ZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiates the effects of radiation in a human non-small cell lung cancer xenograft model. Mol Cancer Ther. 2004;3:977–983. [PubMed]
97. Mauer AM, Cohen EE, Ma PC, Kozloff MF, Schwartzberg L, Coates AI, et al. A phase II study of ABT-751 in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2008;3:631–636. [PubMed]
98. Segreti JA, Polakowski JS, Koch KA, Marsh KC, Bauch JL, Rosenberg SH, et al. Tumor selective antivascular effects of the novel antimitotic compound ABT-751: an in vivo rat regional hemodynamic study. Cancer Chemother Pharmacol. 2004;54:273–281. [PubMed]
99. Natsume T, Watanabe J, Ogawa K, Yasumura K, Kobayashi M. Tumor-specific antivascular effect of TZT-1027 (Soblidotin) elucidated by magnetic resonance imaging and confocal laser scanning microscopy. Cancer Sci. 2007;98:598–604. [PubMed]
100. Yamamoto N, Andoh M, Kawahara M, Fukuoka M, Niitani H. Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative and inhibitor of tubulin polymerization, given weekly to advanced solid tumor patients for 3 weeks. Cancer Sci. 2008 In Press. [PubMed]
101. Bibby MC, Double JA. Flavone acetic acid—from laboratory to clinic and back. Anticancer Drugs. 1993;4:3–17. [PubMed]
102. Zhao L, Ching LM, Kestell P, Kelland LR, Baguley BC. Mechanisms of tumor vascular shutdown induced by 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Increased tumor vascular permeability. Int J Cancer. 2005;116:322–326. [PubMed]

Articles from mAbs are provided here courtesy of Taylor & Francis