NGR-TNF selectively binds to tumor blood vessels via CD13, inducing the activation of caspases and promoting apoptotic endothelial cell death in vivo
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1 AACR 100 th Annual Meeting 2009 Denver NGR-TNF selectively binds to tumor blood vessels via CD13, inducing the activation of caspases and promoting apoptotic endothelial cell death in vivo
2 The NGR-hTNF molecule NGR-hTNF is a novel vascular targeting agent that has been genetically engineered by coupling the N-terminus of human tumor necrosis factor-alpha (htnf-α) with the C- terminus of the tumor-homing peptide Cys-Asn-Gly-Arg-Cys (CNGRC) Cyclic NGR peptide binds selectively to tumour vasculature CD13 de novo expressed on the surface of newly formed tumour blood vessels Resolution: 2.8 Å Human Tumour Necrosis Factor-α Binds to TNF receptors (RI and RII) on vascular endothelium Has strong anti-tumour effect Destroys blood vessel function Is approved as anti-cancer drug, but toxicity limits applications to isolated limb perfusion AACR 100 th Annual Meeting 2009 Denver 2
3 NGR-Qd colocalises with CD13 in tumour vessels CD13/aminopeptidase N is a transmembrane gp CD13 is expressed in: renal, intestinal and liver epithelia nervous system (synaptic membranes and pericytes) myeloid cells angiogenic endothelial cells in blood vessels of varying human tumours, including colon, stomach, pancreas, liver, kidney, lung & pleura, breast and nervous system CD13 + DAPI NGR-Qd + DAPI merge Glioblastoma: frozen section histology AACR 100 th Annual Meeting 2009 Denver 3
4 Binding of both NGR-Qd and NGR-hTNF-Qd is prevented by shrna-cd13 NGR (NGRhTNF)-Qd Anti-CD13 control-qd shrna-cd13 shrna-δn AACR 100 th Annual Meeting 2009 Denver 4
5 In vivo-administered NGR-Qd binds to tumor associated vessels CD31 NGR-Qd merge colon cancer, whole mount histology AACR 100 th Annual Meeting 2009 Denver 5
6 NGR-Qd binds to lung and colon carcinoma blood vessels via CD13 NGR-Qd + CD31 + NGR + control LLC, in vivo administration + anti-cd13 (R3-63) AACR 100 th Annual Meeting 2009 Denver 6
7 NGR-TNF selectively binds to CD13 de novo expressed in tumour vessels via NGR peptide and this binding is necessary to exert antitumour activity 300 NGR-TNF + anti-cd13 (R3-63) Tumour volume (mm 3 ) NGR-TNF + NGR NGR-TNF None Time (days) Adapted from Curnis et al Nat Bioth th International Symposium on Anti-Angiogenic Agents 7
8 In vivo administered NGR-Qd do not bind to normal vessels and tissues (intestine, CNS, kidney, lung, heart, muscle, bone marrow) CD31 CD13 NGR-Qd + CD31 NGR-Qd + CD13 In vivo administered NGR-Qd does not bind to normal intestine, which expresses CD13 AACR 100 th Annual Meeting 2009 Denver 8
9 In vivo administered NGR-Qd binds to vessels during endometrial angiogenesis Endometrium from normal mice CD31 NGR-Qd + CD31 Endometrium from mice in estrus CD31 NGR-Qd + CD31 AACR 100 th Annual Meeting 2009 Denver 9
10 Signaling pathways activated by NGR-hTNF leads to multi-caspase activation inducing apoptotic cell death Densitometric quantification Mek -22 NGR-hTNF anticd13 ng/ml Erk 1/2-33 Pro-CAS-8 NT T NT T NT T NFkB/IkBα -20 CAS-8 Akt -43 Caspases 75 CAS-8 Pro-CAS-3 Mek -11 CAS-3 Erk 1/ Difference over htnf activity (%) NGRh-TNF impairs survival signals through inhibition of MEK, Erk1/2, Akt and NF-kB and the activation of caspases -3, -8 and -9 AACR 100 th Annual Meeting 2009 Denver 10
11 NGR-TNF induces cell death of tumor vessel endothelial cells in vivo CT26 colon carcinoma NGR-TNF TNF Necrotic areas along the tumor vessels are clearly detected 24 h after NGR-TNF administration (100 pg), but not after TNF treatment AACR 100 th Annual Meeting 2009 Denver 11
12 NGR-TNF induces cell death of tumor vessel endothelial cells in vivo CT26 colon carcinoma NGR-TNF TNF Endothelial cell apoptosis (ccl-3 staining) along the tumor vessels is clearly detected 24 h after NGR-TNF administration (100 pg), but not after TNF treatment AACR 100 th Annual Meeting 2009 Denver 12
13 NGR-TNF induces apoptosis of tumor vessel endothelial cells in vivo RMA lymphoma CD31 cleaved caspase 3 merge NGR-TNF none endothelial cell apoptosis (score) p< hours NGR-TNF none p<0.01 p< hours 24 hours Adapted from Crippa et al Cancer Res 2008 AACR 100 th Annual Meeting 2009 Denver 13
14 Conclusions NGR-hTNF is a novel vascular targeting agent coupling the CNGRC peptide to TNF-α The NGR peptide targets a CD13 isoform selectively expressed by endothelial cells of neoangiogenic vessels, including tumour vessels Critical to its selective mechanism of action, NGR does not bind to various CD13-positive epithelial and myeloid cells, and thus does not home to tumour-unrelated tissues The binding of NGR-hTNF to endothelial cells elicits defined signaling pathways through both TNF receptors and CD13, which result in cell death by impairing survival and promoting apoptosis Apoptotic cell death of tumor endothelial cells ultimately impairs tumor growth Indications of this activity comes also from the ongoing clinical phase II studies that will be presented at the ASCO meeting in June AACR 100 th Annual Meeting 2009 Denver 14
15 NGR008: Phase II trial in hepatocellular carcinoma Complete response CT scan of 77-year old male patient with hypervascular, infiltrating HCC Arterial phase Portal phase Complete tumour necrosis after 4 cycles of NGR-hTNF evaluated by contrast-enhanced CT scan in patient refractory to sorafenib February Baseline Source: ASCO GI 2009, Abstract 247 (Poster) AACR 100 th Annual Meeting 2009 Denver May After 4 th cycle NGR-hTNF Clinical development
16 NGR010: Phase II trial in malignant pleural mesothelioma Progression-free survival (preliminary results with weekly schedule) 100 Progression-free survival Weekly (n=14) Triweekly (n=43) 6-month PFS rate: >30% 6-month PFS rate: 17% NGR-hTNF is further developed as single agent in pretreated patients exploring the weekly schedule of administration: preliminary data in malignant pleural mesothelioma suggest a clear benefit in administering NGR-hTNF every week Median PFS reported in literature with BSC: 1.5 months AACR 100 th Annual Meeting 2009 Denver Time (months) Source ANGIO 2009, the 11th International Symposium on Anti-Angiogenic Agents. San Diego February 5-7, 2009
17 Acknowledgements Barbara Valentinis Paola Di Matteo Silvia Tanzarella M Cota C Invernizzi P Mangia F Mingozzi E Tiziano D Zhou A Lambiase C Bordignon Gian-Paolo Rizzardi A Corti and F Curnis (Istituto Scientifico San Raffaele, Milan Italy) A Santoro (Istituto Clinico Humanitas, Milan Italy) F Caligaris-Cappio (Istituto Scientifico San Raffaele, Milan Italy) A Sobrero (Ospedale San Martino, Genoa Italy) C Noberasco (Istituto Europeo di Oncologia, Milan Italy) E Bajetta (Istituto Nazionale dei Tumori, Milan Italy) AACR 100 th Annual Meeting 2009 Denver 17
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