Her2/neu Il ruolo del Pertuzumab - Università degli Studi di Torino
Her2/neu Il ruolo del Pertuzumab - Università degli Studi di Torino
Her2/neu Il ruolo del Pertuzumab - Università degli Studi di Torino
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Università <strong>degli</strong> <strong>Stu<strong>di</strong></strong> <strong>di</strong> <strong>Torino</strong><br />
Corso <strong>di</strong> Laurea Specialistica in Biotecnologie Me<strong>di</strong>che<br />
<strong>Her2</strong>/<strong>neu</strong><br />
<strong>Il</strong> <strong>ruolo</strong> <strong>del</strong> <strong>Pertuzumab</strong><br />
Corso <strong>di</strong> Immunologia Molecolare<br />
Anno Accademico 2007/08<br />
Elisa Migliore
<strong>Her2</strong> nelle neoplasie<br />
Citri A, Yarden Y,<br />
EGF-ERBB<br />
signalling: towards<br />
the systems level,<br />
Nat Rev Mol Cell<br />
Biol, 7:505,2006<br />
• Membro <strong>del</strong>la famiglia dei recettori tirosina chinasi <strong>del</strong>l’EGFR<br />
• Ruolo importante nel promuovere la trasformazione neoplastica e la crescita tumorale<br />
• Significativa correlazione positiva tra la prevalenza <strong>del</strong>l’iperespressione e la progressione<br />
<strong>del</strong>la malattia.
Farmaci in uso clinico contro <strong>Her2</strong><br />
Citri A, Yarden Y, EGF-ERBB signalling: towards the systems level, Nat Rev Mol Cell Biol, 7:505,2006
<strong>Pertuzumab</strong><br />
• Omnitarg / 2C4<br />
• HDIs (Her <strong>di</strong>merization Inhibitors)<br />
• Prodotto nel 1990 dalla Genentech da Fendly<br />
BM* in topi BALB/c immunizzati per <strong>Her2</strong><br />
• MoAb umanizzato<br />
• Genentech – Roche <strong>di</strong> San Francisco<br />
• Cancro <strong>del</strong>la mammella, prostata, polmone,<br />
ovaie e colon-retto<br />
*(Fendly BM et all, Charactirization of murine Monoclonal Antibo<strong>di</strong>es reactive to either the Human Epidermal Growth<br />
Factor Receptor or Her -2/<strong>neu</strong> Gene Product; Cancer Research; 50:1550, 1990)
Interazione <strong>Pertuzumab</strong> – <strong>Her2</strong><br />
• Specificità per <strong>Her2</strong> umano<br />
• Domini I, II, III<br />
• Blocco sterico <strong>del</strong>la regione<br />
necessaria a <strong>Her2</strong> per<br />
<strong>di</strong>merizzare con altri Her<br />
Franklin MC et al, Insights into ErbB signaling from<br />
the structure of the ErbB2-pertuzumab complex,<br />
Cancer Cell, 5:317, 2004
Meccanismo d’azione<br />
• Si legano a due siti <strong>di</strong>fferenti<br />
• In assenza <strong>di</strong> ligando e in iperespressione <strong>di</strong> <strong>Her2</strong> il Trastuzumab e il<br />
<strong>Pertuzumab</strong> arrestano i segnali a valle<br />
Badache A, Hynes NE, A new therapeutic antibody masks ErbB2 to its partners, Cancer Cell, 5:299, 2004
Meccanismo d’azione<br />
• in presenza <strong>di</strong> ligando e con una espressione basale <strong>di</strong> <strong>Her2</strong> <strong>Pertuzumab</strong><br />
riesce ad arrestare i segnali a valle<br />
• l’inibizione <strong>del</strong>la <strong>di</strong>merizzazione è in<strong>di</strong>pendente dai livelli <strong>di</strong> espressione <strong>di</strong><br />
<strong>Her2</strong> (Agus DB et all, Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth,<br />
Cancer Cell, 2:127,2002)<br />
Badache A, Hynes NE, A new therapeutic antibody masks ErbB2 to its partners, Cancer Cell, 5:299, 2004
<strong>Stu<strong>di</strong></strong> clinici<br />
www.roche-trials.com<br />
www.clinicaltrials.gov<br />
• Agus DB et al, Phase I clinical study of pertuzumab, a novel HER<br />
<strong>di</strong>merization inhibitor, in patients with advanced cancer, J Clin Oncol,<br />
23:2534, 2005<br />
• Gordon MS et al, Clinical activity of pertuzumab (rhuMAb 2C4), a HER<br />
<strong>di</strong>merization inhibitor, in advanced ovarian cancer: potential pre<strong>di</strong>ctive<br />
relationship with tumor HER2 activation status, J Clin Oncol, 24:4324-<br />
32, 2006<br />
• Open label, phase II, multicenter study of efficacy and safety for two<br />
<strong>di</strong>fferent doses of a recombinant humanized antibody to <strong>Her2</strong> (rhuMAb<br />
2C4) administered every 3 weeks to patient with metastatic breast<br />
cancer with low expression of <strong>Her2</strong> – (http://roche-trials.com/patient/trialresults/stur117.html)
1) Agus DB et al, Phase I clinical study of pertuzumab, a novel HER<br />
<strong>di</strong>merization inhibitor, in patients with advanced cancer, J Clin<br />
Oncol, 23:2534, 2005<br />
• 21 pazienti con una neoplasia ricorrente o metastatica avanzata durante o dopo la terapia<br />
classica<br />
• età me<strong>di</strong>a 61 aa; Performances Status <strong>di</strong> 0 o 1; aspettativa <strong>di</strong> vita almeno 12 settimane<br />
• tumore <strong>del</strong>la mammella, <strong>del</strong>la prostata, <strong>del</strong> polmone non a piccole cellule, <strong>del</strong>le ovaie, <strong>del</strong><br />
colonretto, <strong>del</strong> pancreas e liposarcomi<br />
• dosi da 0,5 mg/kg a 15 mg/kg (0,5 - 2,0 - 5,0 - 10,0 - 15,0) ogni tre settimane - infusione<br />
intravenosa.<br />
RISULTATI:<br />
• ben tollerato<br />
• nessun anticorpo contro il farmaco<br />
• astenia (63%), vomito (52%), nausea (48%), dolore addominale (48%), <strong>di</strong>arrea (43%),<br />
eruzioni cutanee (43%), anemia (33%).<br />
• vita me<strong>di</strong>a <strong>del</strong> farmaco: 2-4 settimane<br />
• dose efficace superiore a 2,0 mg/kg<br />
• sei pazienti (29%): malattia stabile t ≥ 2,5 mesi.<br />
• due pazienti: risposta parziale al farmaco<br />
• nessuno dei due pazienti iperesprimeva <strong>Her2</strong>.
2) Gordon MS et al, Clinical activity of pertuzumab (rhuMAb<br />
2C4), a HER <strong>di</strong>merization inhibitor, in advanced ovarian<br />
cancer: potential pre<strong>di</strong>ctive relationship with tumor HER2<br />
activation status, J Clin Oncol, 24:4324-32, 2006<br />
• 117 pazienti con tumore avanzato <strong>del</strong>l’ovaio:<br />
corte I - 55 pazienti<br />
corte II - 62 pazienti.<br />
• corte I: dose intravenosa <strong>di</strong> partenza <strong>di</strong> 840 mg seguita da dosi <strong>di</strong> 420 mg<br />
• corte II: dosi intravenose 1050 mg<br />
RISULTATI:<br />
• 5 pazienti: risposta parziale (4,3%)<br />
• 8 pazienti: malattia stabile per almeno sei<br />
mesi (6,8%)<br />
• 10 pazienti: riduzione <strong>del</strong> CA-125 <strong>del</strong> 50%<br />
(14,5%)<br />
• durata me<strong>di</strong>a <strong>di</strong> risposta 18.6 settimane<br />
• sopravvivenza me<strong>di</strong>a corte I 46.7<br />
settimane
• maggiore azione su p<strong>Her2</strong><br />
• effetti collaterali:<br />
<strong>di</strong>arrea (65,6%), vomito (41%),<br />
nausea (41%), dolore addominale<br />
(42,6%), eruzioni cutanee (29.5%)<br />
anemia (14.8%), anoressia<br />
(24.6%), fatica (34.4%).
3) Open label, phase II, multicenter study of efficacy and safety for<br />
two <strong>di</strong>fferent doses of a recombinant humanized antibody to <strong>Her2</strong><br />
(rhuMAb 2C4) administered every 3 weeks to patient with metastatic<br />
breast cancer with low expression of <strong>Her2</strong> – (http://rochetrials.com/patient/trialresults/stur117.html)<br />
• 18 centri, 8 nazioni e 79 pazienti<br />
• tumore alla mammella metastatico esprimente bassi livelli <strong>di</strong> <strong>Her2</strong><br />
• due corti:<br />
- corte I dose intravenosa <strong>di</strong> partenza <strong>di</strong> 840 mg seguita da dosi <strong>di</strong> 420 mg<br />
- corte II ha ricevuto dosi intravenose 1050 mg ogni 3 settimane.<br />
• 6 pazienti eventi<br />
avversi <strong>di</strong> grado<br />
III<br />
• 5 reazioni<br />
avverse<br />
associate<br />
all’infusione <strong>di</strong><br />
grado I
Conclusioni<br />
• La sua capacità <strong>di</strong> agire sulle cellule tumorali attraverso<br />
altri meccanismi non è ancora stata completamente<br />
chiarita, sono state ipotizzate <strong>di</strong>verse attività, quali:<br />
1. abilità <strong>del</strong>la regione Fc <strong>di</strong> ingaggiare il recettore Fcγ <strong>del</strong>le<br />
cellule immuni<br />
2. capacità <strong>di</strong> rompere l’etero<strong>di</strong>mero<br />
• Maggiori stu<strong>di</strong> sono necessari per valutarne l’azione con<br />
altri farmaci, confrontarne i benefici rispetto ad altre terapie<br />
e per identificare quali pazienti maggiormente potrebbero<br />
beneficiare <strong>del</strong> trattamento<br />
L’attività clinica osservata nei vari stu<strong>di</strong>, dove <strong>di</strong>versi pazienti hanno<br />
parzialmente risposto al farmaco, suggerisce che gli inibitori <strong>del</strong>la<br />
<strong>di</strong>merizzazione <strong>di</strong> Her potrebbero essere dei buoni nuovi approcci per il<br />
trattamento <strong>del</strong> cancro.
Bibliografia<br />
1. Franklin, M. C. et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.<br />
Cancer Cell 5, 317–328 (2004).<br />
2. Johnson BE et al, Rationale for a phase II trial of pertuzumab, a HER-2 <strong>di</strong>merization inhibitor, in patients<br />
with non-small cell lung cancer, Clin Cancer Res, 14:4436, 2006<br />
3. Adams CW et al, Humanization of a recombinant monoclonal antibody to produce a therapeutic HER<br />
<strong>di</strong>merization inhibitor, pertuzumab, Cancer Immunol Immunother, 55:717, 2005<br />
4. Nahta R et al, The HER-2-targeting antibo<strong>di</strong>es trastuzumab and pertuzumab synergistically inhibit the<br />
survival of breast cancer cells,Cancer Res, 7:2343, 2004<br />
5. Citri A, Yarden Y, EGF-ERBB signalling: towards the systems level, Nat Rev Mol Cell Biol, 7:505,2006<br />
6. Fendly BM et al, Charactirization of murine Monoclonal Antibo<strong>di</strong>es reactive to either the Human Epidermal<br />
Growth Factor Receptor or Her -2/<strong>neu</strong> Gene Product; Cancer Research; 50:1550, 1990<br />
7. Franklin MC et al, Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex,<br />
Cancer Cell, 5:317, 2004<br />
8. Badache A, Hynes NE, A new therapeutic antibody masks ErbB2 to its partners, Cancer Cell, 5:299, 2004<br />
9. Agus DB et al, Phase I clinical study of pertuzumab, a novel HER <strong>di</strong>merization inhibitor, in patients with<br />
advanced cancer, J Clin Oncol, 23:2534, 2005<br />
10. Gordon MS et al, Clinical activity of pertuzumab (rhuMAb 2C4), a HER <strong>di</strong>merization inhibitor, in advanced<br />
ovarian cancer: potential pre<strong>di</strong>ctive relationship with tumor HER2 activation status, J Clin Oncol, 24:4324-<br />
32<br />
11. www.roche-trials.com<br />
12. www.clinicaltrials.gov<br />
13. Agus DB et al, A potential role for activated HER-2 in prostate cancer, Semin Oncol 27:76, 2000<br />
14. Kim HG et al, EGF receptor signaling in prostate morphogenesis and tumorigenesis, Histol Histopathol<br />
14:1175, 1999<br />
15. Maurer CA et al, Increased expression of erbB3 in colorectal cancer is associated with concomitant<br />
increase in the level of erbB2. Hum Pathol, 29:771, 1998
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