Abstract:Solid tumors have a heterogeneous pathophysiology, which directly affects antibody-targeted therapies. Here, we consider the influence of selected tumor parameters on radioimmunotherapy, by comparing the gross biodistribution, microdistribution, and therapeutic efficacy of either radiolabeled or fluorescently labeled antibodies (A5B7 anti-carcinoembryonic antigen antibody and a nonspecific control) after i.v. injection in two contrasting human colorectal xenografts in MF1 nude mice. The LS174T is moderately/po… Show more
“…Limitations in antibody diffusion within solid tumour masses have previously been reported for reagents used in the IgG format (Adams and Weiner, 2005;Dennis et al, 2007;El Emir et al, 2007a), mainly in relation to the so-called 'antigen barrier'. In this study, we have used antibodies in SIP format (Borsi et al, 2002;Villa et al, 2008), as this format and similar mini-antibody formats have extensively been shown to offer distinctive advantages both for imaging applications (Leyton et al, 2009);von Lukowicz et al, 2007;Wei et al, 2008) and for radioimmunotherapy of cancer (Berndorff et al, 2005;Tijink et al, 2006;Kenanova et al, 2007;Sauer et al, 2009).…”
Section: Discussionmentioning
confidence: 99%
“…administration in the tail vein, we used both fluorescence microscopy and radioactivity-based detection methods. As mouse models of human cancer, we chose LS174T and SW1222 tumours: two colorectal cancer models, which have previously been extensively studied using monoclonal antibodies specific to the carcinoembryonic antigen (El Emir et al, 2007a;Fidarova et al, 2008) and with the vascular-targeting anti-EDB antibody L19 (El-Emir et al, 2007b). Figure 6 shows representative results of a multi-colour fluorescence microscopy analysis of serial sections from LS174T tumours, following i.v.…”
Section: A3 and Cc7 Selectively Target Hypoxic Tumour Regions In Vivomentioning
BACKGROUND: Hypoxia, which is commonly observed in areas of primary tumours and of metastases, influences response to treatment. However, its characterisation has so far mainly been restricted to the ex vivo analysis of tumour sections using monoclonal antibodies specific to carbonic anhydrase IX (CA IX) or by pimonidazole staining, after the intravenous administration of this 2-nitroimidazole compound in experimental animal models. METHODS: In this study, we describe the generation of high-affinity human monoclonal antibodies (A3 and CC7) specific to human CA IX, using phage technology. RESULTS: These antibodies were able to stain CA IX ex vivo and to target the cognate antigen in vivo. In one of the two animal models of colorectal cancer studied (LS174T), CA IX imaging closely matched pimonidazole staining, with a preferential staining of tumour areas characterised by little vascularity and low perfusion. In contrast, in a second animal model (SW1222), distinct staining patterns were observed for pimonidazole and CA IX targeting. We observed a complementary pattern of tumour regions targeted in vivo by the clinical-stage vascular-targeting antibody L19 and the anti-CA IX antibody A3, indicating that a homogenous pattern of in vivo tumour targeting could be achieved by a combination of the two antibodies. CONCLUSION: The new human anti-CA IX antibodies are expected to be non-immunogenic in patients with cancer and may serve as broadly applicable reagents for the non-invasive imaging of hypoxia and for pharmacodelivery applications.
“…Limitations in antibody diffusion within solid tumour masses have previously been reported for reagents used in the IgG format (Adams and Weiner, 2005;Dennis et al, 2007;El Emir et al, 2007a), mainly in relation to the so-called 'antigen barrier'. In this study, we have used antibodies in SIP format (Borsi et al, 2002;Villa et al, 2008), as this format and similar mini-antibody formats have extensively been shown to offer distinctive advantages both for imaging applications (Leyton et al, 2009);von Lukowicz et al, 2007;Wei et al, 2008) and for radioimmunotherapy of cancer (Berndorff et al, 2005;Tijink et al, 2006;Kenanova et al, 2007;Sauer et al, 2009).…”
Section: Discussionmentioning
confidence: 99%
“…administration in the tail vein, we used both fluorescence microscopy and radioactivity-based detection methods. As mouse models of human cancer, we chose LS174T and SW1222 tumours: two colorectal cancer models, which have previously been extensively studied using monoclonal antibodies specific to the carcinoembryonic antigen (El Emir et al, 2007a;Fidarova et al, 2008) and with the vascular-targeting anti-EDB antibody L19 (El-Emir et al, 2007b). Figure 6 shows representative results of a multi-colour fluorescence microscopy analysis of serial sections from LS174T tumours, following i.v.…”
Section: A3 and Cc7 Selectively Target Hypoxic Tumour Regions In Vivomentioning
BACKGROUND: Hypoxia, which is commonly observed in areas of primary tumours and of metastases, influences response to treatment. However, its characterisation has so far mainly been restricted to the ex vivo analysis of tumour sections using monoclonal antibodies specific to carbonic anhydrase IX (CA IX) or by pimonidazole staining, after the intravenous administration of this 2-nitroimidazole compound in experimental animal models. METHODS: In this study, we describe the generation of high-affinity human monoclonal antibodies (A3 and CC7) specific to human CA IX, using phage technology. RESULTS: These antibodies were able to stain CA IX ex vivo and to target the cognate antigen in vivo. In one of the two animal models of colorectal cancer studied (LS174T), CA IX imaging closely matched pimonidazole staining, with a preferential staining of tumour areas characterised by little vascularity and low perfusion. In contrast, in a second animal model (SW1222), distinct staining patterns were observed for pimonidazole and CA IX targeting. We observed a complementary pattern of tumour regions targeted in vivo by the clinical-stage vascular-targeting antibody L19 and the anti-CA IX antibody A3, indicating that a homogenous pattern of in vivo tumour targeting could be achieved by a combination of the two antibodies. CONCLUSION: The new human anti-CA IX antibodies are expected to be non-immunogenic in patients with cancer and may serve as broadly applicable reagents for the non-invasive imaging of hypoxia and for pharmacodelivery applications.
“…Although we did not have a nonspecific radiolabeled antibody ( 131 I-IgG1/MOPC) control in our studies, we have previously shown no therapeutic effect with a dose of 4 MBq of 131 I-IgG1/ MOPC in SW1222 tumor metastases (16), suggesting that cross-fire irradiation from circulating antibody does not significantly affect tumor growth. Moreover, our current studies show that 10 d after administration, the tumor-to-blood ratio of huA5B7 is approximately 8:1 in SW1222 tumors with minimal blood levels, which supports the hypothesis that the observed therapeutic effects were due to tumor-bound antibody rather than circulating antibody.…”
Section: Discussionmentioning
confidence: 96%
“…HuA5B7 was provided by UCB Pharma S.A. and labeled with 131 I ( 131 I-huA5B7) (Perkin Elmer, U.K.) using the IODO-GEN (Pierce) method as previously described (16,17). Labeling yield and radiochemical purity were assessed by thin-layer chromatography (silica gel Si60, stationary phase; 80% methanol, mobile phase); antigen binding of the radiolabeled antibody was compared with nonlabeled huA5B7 and assessed by enzyme-linked immunosorbent assay.…”
Section: Agents and Antibody Labelingmentioning
confidence: 99%
“…CEA expression was confirmed in all tumor models as previously described (16). Markers of DNA damage response (gH2AX and DNA-PK), cell cycle (phospho-histone H3, cyclin B1), proliferation (Ki-67), and apoptosis (caspase-3) were examined in tumor sections from each group at 2, 6, and 10 d after treatment initiation.…”
Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced disease offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. We evaluated the preclinical efficacy of combination radioimmunotherapy, using a humanized 131 Ilabeled anti-carcinoembryonic antigen antibody ( 131 I-huA5B7), with cetuximab in colorectal cancer (CRC). Methods: Three human CRC cell lines-SW1222, LoVo, and LS174T-were used to generate subcutaneous xenografts, and stably luciferase-transfected SW1222 cells were used to establish a model of hepatic metastases in immunocompromised mice. Imaging and biodistribution studies were conducted to confirm the selective tumor localization of 131 I-huA5B7. Efficacy was evaluated on the basis of tumor growth delay and survival, along with markers of DNA damage response, cell cycle, proliferation, and apoptosis. Results: Selective tumor targeting was achieved with 131 IhuA5B7 alone or in combination with cetuximab without observable toxicity. Compared with monotherapy, combining cetuximab with radioimmunotherapy significantly and synergistically reduced tumor growth and prolonged survival of mice in 2 of the subcutaneous and in the metastatic tumor model. Evidence of DNA damage, G2/M arrest, significantly decreased proliferation, and increased apoptosis were observed with radioimmunotherapy and the combination therapy. However, a significant decrease in DNA-protein kinase expression with the combination regimen suggests that the addition of cetuximab suppressed DNA repair. Conclusion: Our results demonstrate enhanced therapeutic efficacy with the combination of cetuximab and radioimmunotherapy in CRC, which could potentially translate into successful clinical outcomes. This strategy could improve the treatment of residual disease postoperatively and ultimately prevent or delay recurrence. Furthermore, other carcinoembryonic antigen-expressing malignancies could also benefit from this approach.
Mithilfe einer hoch effizienten und schnellen CuII‐katalysierten Dreikomponenten‐„Klickreaktion“ gelang der Aufbau von dualen optischen Markierungsreagentien. In ersten Bildgebungsversuchen konnte die Verteilung des damit markierten Antikörpers A5B7 vom zellulären bis zum makroskopischen Niveau mit einer Kombination aus optischen und radiometrischen Techniken verfolgt werden.
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