Graeme J O'Keefe

Graeme J O'Keefe
University of Melbourne | MSD · Department of Medicine

Ph.D

About

251
Publications
19,520
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
9,830
Citations

Publications

Publications (251)
Article
Background The introduction of therapeutics for Alzheimer's disease has led to increased interest in precisely quantifying amyloid-β (Aβ) burden for diagnosis, treatment monitoring, and further clinical research. Recent positron emission tomography (PET) hardware innovations including digital detectors have led to superior resolution and sensitivit...
Article
Full-text available
Background New generation PET scanners achieve superior resolution and sensitivity, but the implications on beta amyloid (Aβ) quantitation are not well understood. The Centiloid (CL) scale (Klunk et al., 2015) was introduced to promote consistent Aβ burden quantification across different positron emission tomography (PET) tracers and quantification...
Article
The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We developed a novel tumor-specific anti-EGFR chimeric antib...
Article
Introduction: Anti-ASCT2 antibody drug conjugate (ADC) MEDI7247 has been under development as a potential anti-cancer therapy for patients with selected relapsed/refractory hematological malignancies and advanced solid tumors by MedImmune. Although promising efficacy was observed in the clinic, pharmacokinetic (PK) analyses observed low exposure o...
Article
Background The Centiloid (CL) scale allows quantification of amyloid‐b accumulation across multiple PET tracers for the diagnosis of Alzheimer’s disease. The CL quantification on different PET cameras may result in significant quantification bias when merging cohorts acquired from multiple cameras or in the longitudinal studies when change of camer...
Article
The Centiloid (CL) scale allows quantification of amyloid‐b accumulation across multiple PET tracers for the diagnosis of Alzheimer’s disease. The CL quantification on different PET cameras may result in significant quantification bias when merging cohorts acquired from multiple cameras or in the longitudinal studies when change of camera occurs. I...
Article
Introduction Tissue transglutaminase 2 (TG2) is a calcium-dependent enzyme which cross-links proteins. It is overexpressed in many diseases and plays a key role in tissue remodeling, including cell adhesion and migration. Overexpression of TG2 in breast cancer is a marker for patients at risk of recurrence. Non-invasive imaging of TG2 can therefore...
Article
Full-text available
Ephrin type-A 2 (EphA2) is a transmembrane receptor expressed in epithelial cancers. We report on a phase I dose escalation and biodistribution study of DS-8895a, an anti-EphA2 antibody, in patients with advanced EphA2 positive cancers. DS-8895a was administered at 1, 3, 10 or 20 mg/kg every 2 weeks to determine safety, pharmacokinetics and anti-tu...
Article
Full-text available
Positron emission tomography is the imaging modality of choice when it comes to the high sensitivity detection of key markers of thrombosis and inflammation, such as activated platelets. We, previously, generated a fluorine-18 labelled single-chain antibody (scFv) against ligand-induced binding sites (LIBS) on activated platelets, binding it to the...
Article
Full-text available
Purpose A method for calculating nuclear medicine ionization chamber (NMIC) calibration settings with a Monte Carlo model is presented and validated against physical measurements. This work provides Monte Carlo–calculated calibration settings for select isotopes with no current manufacturer recommendations and a method by which NMIC manufacturers o...
Article
Background Centiloid (CL) is a semiquantitative measure of amyloid‐β burden based on the ratio between neo‐cortical target region and the whole cerebellum. Photon scatter is one of the major sources of noise in PET data. Scatter correction methods are very different across PET cameras. In this study, we investigate how scatter correction affects th...
Article
Full-text available
Purpose Τhis study aimed to optimize the ⁸⁹Zr-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of ⁸⁹Zr-Df-bintrafusp alfa and ⁸⁹Zr-Df-control radioconjugates. Methods Bintrafusp alfa (anti-PD-L1 human IgG1 antibody fused to TGF-β receptor II (TGF-βRII), avelumab (ant...
Article
Full-text available
Background The adverse impact of increasing brain tumor size on the efficacy of antibody drug conjugates (ADCs) was investigated preclinically then validated with clinical data. Methods Preclinical study: The impact of tumor size on ADC tumor delivery and treatment response was evaluated in an EGFR-amplified patient derived glioblastoma (GBM) mode...
Conference Paper
Overview Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years.1 EphA3 is a tumor restricted antigen expressed in various solid tumors and the tumor vasculature of 100% of GBM.2,3 Ifabotuzumab is a non-fucosylated IgG1κ humaneered antibody targeting the EphA3 receptor.4 A P...
Article
Purpose: A method for calculating nuclear medicine ionisation chamber (NMIC) calibration settings with a Monte Carlo model is presented and validated against physical measurements. This work provides Monte Carlo calculated calibration settings for select isotopes with no current manufacturer recommendations and a method by which NMIC manufacturers...
Article
Full-text available
Background: A research priority in finding a cure for HIV is to establish methods to accurately locate and quantify where and how HIV persists in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). Infusing copper-64 (64Cu) radiolabelled broadly neutralising antibodies targeting HIV envelope (Env) with CT scan and pos...
Article
Aims To evaluate diagnostic performance of glomerular filtration rate (GFR) estimated by modification of diet in renal disease (MDRD), chronic kidney disease epidemiology collaboration (CKD-EPI), full age spectrum (FAS), and revised Lund-Malmo (r-LM) equations in adults with diabetes. Methods Individuals were included in this cross-sectional study...
Article
Full-text available
Through protein engineering and a novel pegylation strategy, a diabody specific to tumor-associated glycoprotein 72 (TAG-72) (PEG-AVP0458) has been created to optimize pharmacokinetics and bioavailability to tumor. We report the preclinical and clinical translation of PEG-AVP0458 to a first-in-human clinical trial of a diabody. Methods: Clinical tr...
Article
Full-text available
Background: 4-[18F] fluorobenzyl dexetimide (F-DEX) is the first non-subtype selective fluorine-18 labelled tracer for muscarinic receptors (mAChR) used in humans. A recent first-in-human study found high regional brain uptake with low variation in normal subjects. Disturbance of mAChR has been reported in Alzheimer's and Parkinson's disease, schi...
Article
Full-text available
Introduction Tumor hypoxia is a centerpiece of disease progression mechanisms such as neoangiogenesis or aggressive hypoxia-resistant malignant cells selection that impacts on radiotherapy strategies. Early identification of regions at risk for recurrence and prognostic-based classification of patients is a necessity to devise tailored therapeutic...
Article
Objective: To test the hypothesis that neuroinflammation is a key process in adult Niemann-Pick type C (NPC) disease, we undertook PET scanning utilizing a ligand binding activated microglia on 9 patients and 9 age- and sex-matched controls. Method: We scanned all participants with the PET radioligand 11C-(R)-PK-11195 and undertook structural MR...
Article
Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm. EphA3 is a tumor restricted antigen expressed in 38–40% of GBM and 100% of the tumor vasculature. Ifabotuzumab is a non-fucosylated IgG1κ antibody targeting EphA3 receptor. A Phase 1 study of ifabotuzumab in haematological malignancies was well tolerated and clinically activ...
Conference Paper
Overview: Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years (1). EphA3 is a tumor restricted antigen expressed in 38-40% of GBM and 100% of the tumor vasculature (2, 3). Ifabotuzumab is a non-fucosylated IgG1K antibody targeting EphA3 receptor (4). A Phase I study of ifabotuzumab...
Conference Paper
Overview: Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years (1). EphA3 is a tumor restricted antigen expressed in 38-40% of GBM and 100% of the tumor vasculature (2, 3). Ifabotuzumab is a non-fucosylated IgG1K antibody targeting EphA3 receptor (4). A Phase I study of ifabotuzumab...
Article
Full-text available
B7-H3 is a transmembrane protein widely expressed in a variety of cancers and has been shown to play a role in anti-tumor immunity. This study aims to develop a molecular imaging probe to identify B7-H3 expression in tumors and to develop ⁸⁹Zr-DS-5573a as a theranostic that could aid patient selection in clinical Phase I studies. Methods: The anti-...
Article
Full-text available
AIMS: We report the discovery of a systematic miscalibration during the work-up process for site validation of a multi-centre clinical PET imaging trial using 68Ga, which manifested as a consistent and reproducible underestimation in the quantitative accuracy (assessed by SUV) of a range of PET cameras from different manufacturers at a number of di...
Article
Full-text available
We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [¹¹C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (¹¹C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients...
Article
Full-text available
Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [¹¹C]Pittsburgh Compound B ([¹¹C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including Alzheimer’s disease, and healthy volunteers. The method...
Article
Full-text available
Background: DS-8273a, an anti-human death receptor 5 (DR5) agonistic antibody, has cytotoxic activity against human cancer cells and induces apoptosis after specific binding to DR5. DS-8273a is currently being used in clinical Phase I trials. This study evaluated the molecular imaging of DR5 expression in vivo in mouse tumor models using SPECT/CT a...
Article
The significance of imaging hypoxia with the positron emission tomography ligand [(18) F]FMISO has been demonstrated in a variety of cancers. However, the slow kinetics of [(18) F]FMISO require a 2-h delay between tracer administration and patient scanning. Labeled chloroethyl sulfoxides have shown faster kinetics and higher contrast than [(18) F]F...
Article
Full-text available
Alzheimer’s disease (AD) is a degenerative brain disorder and is the most common form of dementia. Minimally invasive approaches are required that combine biomarkers to identify individuals who are at risk of developing mild cognitive impairment (MCI) and AD, to appropriately target clinical trials for therapeutic discovery as well as lifestyle str...
Article
Full-text available
// David W. Greening 1,* , Sze Ting Lee 2,3,4,* , Hong Ji 1 , Richard J. Simpson 1 , Angela Rigopoulos 3,4 , Carmel Murone 3,4 , Catherine Fang 3,4 , Sylvia Gong 2 , Graeme O’Keefe 2,3,4 and Andrew M. Scott 2,3,4,* 1 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia 2 Depart...
Conference Paper
Full-text available
Aims: The aim of the study was to explore Fc mutations of a humanized anti-Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. Methods: Four hu3S193 variants (I253A, H310A, H435A and I253A/ H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes iodine-...
Article
IgG has a long half-life through engagement of its Fc region with the neonatal Fc receptor (FcRn). The FcRn binding site on IgG1 has been shown to contain I253 and H310 in the CH2 domain and H435 in the CH3 domain. Altering the half-life of IgG has been pursued with the aim to prolong or reduce the half-life of therapeutic IgGs. More recent studies...
Article
Full-text available
Background: The aim of the study was to explore Fc mutations of a humanised anti-Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. Methods: Four hu3S193 variants (I253A, H310A, H435A and I253A/H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes...
Article
Full-text available
Methods: DS-8895a was labeled with (111)In, (125)I and (89)Zr, and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen binding affinity (Scatchard analysis) and serum stability in vitro. In vivo biodistribution, imaging and pharmacokinetic studies were performed, with SPECT/MR and PET/MR imaging undertaken. A dose-escala...
Article
Full-text available
Angiogenesis and epidermal growth factor receptor (EGFR) inhibition has been shown to have anti-tumour efficacy, and enhance the therapeutic effects of cytotoxic chemotherapy in metastatic colorectal cancer. The interplay of signalling alterations and changes in metabolism and hypoxia in tumours following anti-VEGF and anti-EGFR treatment is not we...
Article
With the aim of preparing hypoxia-selective imaging and therapeutic agents, technetium(I) and rhenium(I) tricarbonyl complexes with pyridylhydrazone, dipyridylamine, and pyridylaminocarboxylate ligands containing nitrobenzyl or nitroimidazole functional groups have been prepared. The rhenium tricarbonyl complexes were synthesized with short reactio...
Article
Full-text available
Background: The development of antibody therapeutics for imaging and payload delivery is complex, and intact IgG have long half-lives that impact on tumor:blood ratios and tumor penetrance. Smaller molecular weight antibody constructs (eg diabodies) have been developed for improved penetrance into tumor, faster blood clearance, and enhanced tumor:...
Article
Full-text available
To investigate and compare the quantitative accuracy of (90)Y imaging across different generation PET/CT scanners, for the purpose of dosimetry after radioembolization with resin microspheres. A strict experimental and imaging protocol was followed by 47 international sites using the NEMA 2007/IEC 2008 PET body phantom with an 8-to-1 sphere-to-back...
Conference Paper
L-tyrosine confers greater residualizing properties to a D-amino acid rich residualizing peptide for radioiodination of internalizing antibodies Lee FT, Burvenich IJG, Guo N, Kocovski P, Tochon-Danguy H, Ackermann U, O'Keefe GJ, Song S, Rigopoulos A, Liu Z, Gan HK, Scott AM 1Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and the...
Conference Paper
Full-text available
Background:The use of smaller molecular weight antibody constructs (eg diabodies) has great promise for antibody therapeutics for improved penetrance into tumor, faster blood clearance, and enhanced tumor: normal tissue uptake, however renal uptake may impact on imaging and therapeutic effects.We have developed a novel pegylated diabody toTAG-72 (A...
Conference Paper
[Background] A phase I first-in-human clinical trial of 124I-PEGAVP0458 in patients with TAG-72 positive ovarian or prostate cancer has been carried out to determine the tumour targeting potential of PEGAVP0458, a diabody containing the modified CC49 antibody sequences. This study aimed to elucidate the biodistribution, estimate the tracer kinetics...
Conference Paper
Background and aim: Deterioration of bone occurs rapidly after stroke, leading to increased risk of fracture and worsening outcomes for stroke survivors. Two complementary studies have been designed with aligned comorbidities and key outcomes, using humans and animal models. We aim to determine the timing and magnitude of bone loss after stroke and...
Article
Full-text available
The wireless capsule endoscope (WCE) is a first-line medical tool for the diagnosis of many gastrointestinal (GI) tract diseases such as obscure GI bleeding, Crohn’s disease, small bowel tumors, and Celiac disease. Over the past few years, significant research attention has been paid to upgrading the WCE from a diagnostic-only tool to an active med...
Conference Paper
Full-text available
Objective: Radiolabelled-Choline PET has shown promise in detection and localization of dominant intraprostatic lesions. The aim of the study was to evaluate the kinetics of [C-11]Choline uptake in prostate tumours, in addition to the semi-quantitative analysis using the standardised uptake value (SUV). Methods: [C-11]Choline dynamic PET studies...
Conference Paper
Full-text available
Objective: The aim of the study was to quantitatively analyse the [F-18]FLT and [F-18]FLETT tracer uptakes in A431 tumours and its correlation with corresponding pixel intensities of T2-weighted tumour images via nanoPET/MRI imaging studies. Methods: Three female BALB/c nude mice bearing A431 tumours were treated with 1 mg Cetuximab three times...
Article
Imaging of activated platelets using an activation specific anti GPIIb/IIIa integrin single-chain antibody (scFvanti-LIBS) conjugated to a positron emitting copper-64 complex of a cage amine sarcophagine chelator (MeCOSar) is reported. This tracer was compared in vitro to a 64CuII complex of the scFv conjugated to another commonly used macrocycle,...
Conference Paper
Full-text available
CT is a novel technique for visualizing and quantifying porosity and pore connectivity of soils. Allows high resolution, three-dimensional, non-destructive imaging of heterogeneous soils and permits actual, rather than inferred, soil pore characteristics. Limited information is available on the optimum sampling core diameter for measuring soil poro...
Article
The scalable XCAT voxelised phantom was used with the GATE Monte Carlo toolkit to investigate the effect of voxel size on dosimetry estimates of internally distributed radionuclide calculated using direct Monte Carlo simulation. A uniformly distributed Fluorine-18 source was simulated in the Kidneys of the XCAT phantom with the organ self dose (kid...
Article
Animal studies suggest that serotonin, mediated by the 5-HT1A receptor, plays a key role in spatial learning and memory. The role of serotonin in spatial memory in humans has, however, been less well studied. This study examined the relationship between serotonin receptor density in the human brain and spatial learning and memory using the 5-HT1A r...
Article
[(18)F]FMISO is the most widely validated PET radiotracer for imaging hypoxic tissue. However, as a result of the pharmacokinetics of [(18)F]FMISO a 2h wait between tracer administration and patient scanning is required for optimal image acquisition. In order to develop hypoxia imaging agents with faster kinetics, we have synthesised and evaluated...
Article
Full-text available
Objectives: The ability to measure cellular proliferation non-invasively in renal cell carcinoma may allow prediction of tumour aggressiveness and response to therapy. The aim of this study was to evaluate the uptake of 18F-fluorothymidine (FLT) PET in renal cell carcinoma (RCC), and to compare this to 18F-fluorodeoxyglucose (FDG), and to an immun...
Article
Full-text available
huA33 is a humanized antibody that targets the A33 antigen, which is highly expressed in intestinal epithelium and more than 95% of human colon cancers but not other normal tissues. Previous studies have shown huA33 can target and be retained in a metastatic tumor for 6 wk but eliminated from normal colonocytes within days. This phase I study used...
Article
The Non-Invasive Arterial Monitor (NIAM3) is an SiPM based detector system designed for calibrating Positron-Emission Tomography (PET) images without invasive blood sampling. By imaging the radial and ulnar arteries in the wrist directly with a custom built PET system the resultant PET images can be calibrated. An integral step in the development o...
Article
Biomarkers for Alzheimer disease (AD) can detect the disease pathology in asymptomatic subjects and individuals with mild cognitive impairment (MCI), but their cognitive prognosis remains uncertain. We aimed to determine the prognostic value of β-amyloid imaging, alone and in combination with memory performance, hippocampal atrophy, and apolipoprot...
Article
Full-text available
CS-1008 (tigatuzumab), an anti-human death receptor 5 (DR5) agonist induces apoptosis and has cytotoxic activity against human cancer cell lines. This study reports on the preclinical validation of (111)In-labeled anti-DR5 humanised antibody CS-1008 as a diagnostic tool to study the DR5 occupancy in cancer patients, and establish dose ranges for re...
Article
Full-text available
CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to human death receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC). Patients with mCRC who had rec...
Article
2583 Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody (Ab) to human DR5 created by CDR grafting of the murine Ab TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative...
Article
Purpose CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to human death receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC). Patients and Methods...
Article
Background: This study investigates the use of (18)F-fluoromisonidazole (FMISO) PET-guided radiotherapy dose painting for potentially overcoming the radioresistant effects of hypoxia in head and neck squamous cell carcinoma (HNSCC). Material and methods: The study cohort consisted of eight patients with HNSCC who were planned for definitive radi...