Andrew M Scott

..abstract:..

..This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials...

..To determine the in vivo characteristics of huA33, a CDR-grafted humanized antibody against the A33 antigen, we have conducted an open-label, dose escalation, biopsy-based phase I trial of huA33 in patients with colorectal carcinoma...

..These in vitro and in vivo characteristics of ch806 distinguish it from all other antibodies targeting EGFR...

..We report a first-in-man trial of a humanized antibody (hu3S193) against the Le(y) antigen...

..Positron emission tomography (PET) was evaluated in low-grade non-Hodgkin lymphoma (NHL) to determine its impact on staging and management and to compare PET and gallium scans...

..Secondary aims were to determine the incremental staging information provided by PET and to document the effect of PET on treatment outcomes...

..The aims of our study were to examine the impact of PET in changing management in patients with proven or suspected colorectal cancer recurrence and to assess the impact of management change on disease-free survival...

..The ability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 and docetaxel chemotherapy to enhance the efficacy of RIT was also assessed in vivo...

..Further investigations of dosing regimens using EGFR tyrosine kinase inhibitors and radioimmunotherapy in the treatment of EGFR expressing tumors are warranted...

..Therefore, we have investigated the efficacy of the alpha-particle-emitting bismuth-213 (213Bi) radioimmunotherapy using the humanized anti-Lewis Y (Ley) monoclonal antibody humanized 3S193 (hu3S193)...

..Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic...

..However, limited in vitro stability and high renal localization of radiolabeled constructs were observed, which, despite the observed tumor targeting of the hu3S193 multimer, most likely preclude its use in RIT and imaging modalities...

..This information was used to optimize the therapeutic synergy between mAb 806 and AG1478 in a xenograft model...

..These results highlight the potential use of mAb 806 for generation of conjugates suitable for diagnostic and therapeutic use in patients with EGFR-positive malignancies...

..Finally, our observations suggest that the generation of antibodies to transitional forms of growth factor receptors may represent a novel way of reducing normal tissue targeting yet retaining antitumor activity...

..The aim of this study was to develop a PET-based method for detecting the constitutively active mutant de2-7 EGFR, which is associated with disease progression and resistance to chemotherapy and radiotherapy in glioma...

..To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using (11)C-choline positron emission tomography PET scans in patients with localized prostate cancer...

..No antitumour responses were observed. In conclusion, weekly cG250 with daily low-dose subcutaneous IL-2 is well tolerated. IL-2 does not influence cG250 biodistribution or increase HACA...

..These findings have direct implications in understanding the role of angiogenesis and hypoxia in NSCLC biology...

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..We have previously shown that mAb 806, a novel EGFR-specific antibody, is able to inhibit the growth of U87MG.Δ2-7 glioma xenografts expressing the de2-7 EGFR and may have potential as a therapeutic...

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..This study supports the use of humanized gene-modified T cells as a potential therapy for Le(Y+) malignancies...

..18F-FMISO PET may have a role not only in directing patients toward targeted hypoxic therapies but also in monitoring response to such therapies...

..We report on a novel method for human renal tumour transplants using an automated biopsy gun to obtain tumour tissue and an epidural needle with introducer to easily deploy the grafts under the renal capsule...

..The favourable immune properties of KM871, combined with this preliminary clinical data, indicate that KM871 has potential for the treatment of metastatic melanoma...

..Factors affecting the efficacy of therapeutic monoclonal antibodies (mAb) directed to the epidermal growth factor receptor (EGFR) remain relatively unknown, especially in glioma...

..CONCLUSION: Radioimmunotherapy using 131I-huA33 shows promise in targeting colorectal tumors, and is deliverable at a maximum tolerated dose of 40 mCi/m2. Further studies of 131I-huA33 in combination with chemotherapy are planned...

..As our observations are likely to apply to other receptors overexpressed in cancer, they suggest a strategy for developing antitumor antibodies even when the target receptor is expressed in normal tissue...

..These results establish the antitumor efficacy of the EGFR inhibitor AG1478 and provide a rationale for its clinical evaluation in combination with both chemotherapy and other EGFR therapeutics...

..This observation is directly relevant to glioma where de2-7 and wt EGFR appear to be coexpressed. Thus, expression of de2-7 EGFR in BaF/3 cells provides an in vitro model for evaluating the signalling pathways activated by this receptor...

..5 mmHg. Further direct studies of renal tumour oxygenation combined with therapies directed towards hypoxia may allow a better understanding of the relationship between 18F-FMISO results and the biological significance of hypoxia in RCC...

..This review discusses the relevance and biology of hypoxia in cells and organ systems, and reviews the laboratory and clinical applications of (18)F-FMISO in oncology and noncancer disease states...

..This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC)...

..Furthermore, ADCC was significantly reduced using NK-depleted PBMCs. These results suggest combining IL-2 or IL-12 with KM871 may enhance KM871 immune-mediated cell killing in patients with metastatic melanoma...

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..Consequently, inhibition of a dominant oncogene by targeted therapy can alter the hierarchy of RTKs resulting in rapid therapeutic resistance...

..In conclusion, repeated intravenous doses of up to 50 mg/m(2) of cG250 are safe. Furthermore cG250 has a long half-life and targets clear cell RCC effectively...

..These findings show the biological importance of EphA3/ephrin-A5 interactions and that ephrin-A5 and IIIA4 have great potential as tumor targeting reagents...

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..This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti-Lewis Y (Le(y)) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Le(y) antigen...

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..These cost savings remain robust over a wide range of disease prevalence and FDG-PET costs...

..Thus, the mitochondrial localisation of de2-7EGFR contributes to its tumorigenicity and might help to explain its resistance to some EGFR-targeted therapeutics...

..To prospectively evaluate the use of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) in the initial staging of squamous cell head and neck carcinoma...

..Given the increase in VEGF, we combined mAb 806 with bevacizumab in vivo, resulting in additive activity...

..The results reveal new modes of receptor-antibody interactions for EGFR and de2-7-EGFR...

..To evaluate the accuracy of (11)C-choline PET scans in defining dominant intraprostatic lesions (DILs) for radiotherapy target volume definition...

..3+/-2.1% (n=3; not decay corrected) and an average specific radioactivity of 40 GBq/micromol (1.1 Ci/micromol) at the end of synthesis. The total synthesis time from EOB including HPLC purification and formulation was 45 min...

..In the future, analysis of FDG PET data in specific subpopulations of children with refractory epilepsy may lead to novel insights regarding aetiology...

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..CONCLUSION: FDG-PET has an important role in guiding the management of patients with advanced melanoma, particularly when surgery is contemplated...

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..We evaluated whether 18F-FDG-PET altered stage classification, management, and prognostic stratification of newly diagnosed small cell lung cancer (SCLC)...

..This article summarizes the current diagnostic and therapeutic use of radioisotopes for bony disease in prostate cancer with particular reference to radionuclide bone scintigraphy and positron emission tomography...

..Molecular imaging assessments, including changes in (18)F-deoxyglucose (FDG) or (18)F-deoxythymidine (FLT) uptake by positron emission tomography (PET), may provide earlier, more robust evaluation of treatment efficacy...

..These findings suggest mesocortical dopamine inputs via D(1) receptors may play a role in the aetiology of OCD...

..This concept of conformational epitope targeting by antibodies reflects an underlying interplay between the structure and biology of different conformational forms of the EGFR family...

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..A humanized Le(y)-specific antibody (hu3S193) has shown encouraging safety, pharmacokinetic and tumor-targeting properties in recently completed Phase I clinical trials...

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..In an unplanned analysis, vaccinated patients appeared to have superior clinical outcomes to those treated with placebo or protein alone. The vaccine is safe and highly potent immunologically...

..Thus, MAb 806 can be used to target tumor cells containing amplification of the EGFR gene or de2-7 EGFR but does not bind to the wild type EGFR when expressed on the cell surface...

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..Closely related blood-group determinants (Le(a) and Le(b)) cannot enter the specificity pocket, making the Le(y) antibodies promising candidates for immunotherapy of epithelial cancer...

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..01] and 3.4 microSv [P = 0.03], respectively). CONCLUSION: The radiation doses currently received by technologists working in PET are within accepted occupational health guidelines, but improved shielding can further reduce the dose...

..Quantitation of uptake of FMISO showed a tumor/brain ratio of 1.9 and a tumor/blood ratio of 2.6 at 2 hours post injection...

..Assessment of glucose metabolism with FDG PET might represent a more powerful tool to detect bone metastases in lung cancer compared with conventional bone scans...

..Our results indicate that CHP-HER2 induced HER2-specific humoral responses in patients with HER2-expressing tumors and that GM-CSF seems to accelerate the responses...

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..These data warrant transfer of the anti-FAP-TNF immunocytokine into clinical trials for the treatment of FAP-positive tumors...

..The purpose of this study was to evaluate the safety, pharmacokinetics and dosimetry of four increasing doses of (99m)Tc-DI-80B3 Fab' in healthy volunteers...

..In translational research, [18F]fluorodeoxyglucose probes have been designed to optimize the detection of melanoma tumor sites in vivo...

..In this article, we review the role of nuclear medicine in the assessment of malignant melanoma...

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..CONCLUSIONS: CHP-HER2 vaccine was safe and induced HER2-specific CD8(+) and/or CD4(+) T-cell immune responses...

..The purpose of the study was to evaluate [(18)F]fluoromisonidazole (FMISO) PET in advanced head and neck cancer during hypoxia-targeting therapy...

..A phase I trial of humanized 3S193 (hu3S193) with dosing up to 40 mg/m2 demonstrated tumor targeting without serious toxicities or the development of human anti-human antibodies...

..Our study also indicates that DeltaEGFR is restricted to glioblastoma, in contrast to other reports that this mutation is found in tumors outside the brain...

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