3/5/2016. Radiochemistry and PET imaging with 89 Zr: Methodology, Preclinical Analysis and Clinical Applications. Disclosures
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1 Disclosures Suzanne Lapi declare no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. Radiochemistry and PET imaging with Zr: Methodology, Preclinical Analysis and Clinical Applications Suzanne Lapi, Associate Professor of Radiology Self-Assessment Question 1 Imaging with radiolabeled antibodies could potentially be used for: A. Stratifying patients who might benefit from antibody therapy B. Monitoring the course of therapy C. Paving the way for the next generation of targeted therapeutics D. All of the above Self-Assessment Question 2 What chelator is typically used for Zr chemistry? A. EDTA B. NOTA C. DFO D. DTPA Self-Assessment Question 3 The half life of Zr is A. 110 minutes B. 3.3 days C. 8 days D. 60 days Self-Assessment Question 4 Pre release quality control criteria for Zr antibody includes A. Immunoreactivity B. Sterility C. Ethanol content D. Endotoxin 1
2 Self-Assessment Question 5 Imaging of HER2 status in breast cancer patients may provide insight into: A. Determining which patents may benefit from antibody therapy B. Tumor metabolic function C. Determining which patients may be resistant to radiotherapy D. Tumor oxygen tension Positron Emission Tomography PET imaging is a very sensitive tool capable of providing quantitative information about biochemical and physiological processes in a noninvasive manner. Glucose Fluorodeoxyglucose (FDG) 59 year old woman with T-cell lymphoma Why develop new imaging agents? Imaging more than detection of cancer. Imaging can provide more information: detection, prediction of treatment response, receptor status, oxygenation, microenvironment Initial study 4 months later, after chemotherapy Different information can be obtained using different tracers Imaging with Antibodies: + [ 18 F]FDG [ 68 Ga]DOTATOC Specificity Sensitivity Clinical Nuclear Medicine. 38(4): , April
3 Why Antibodies? How to pick a radioisotope? Antibodies (and/or fragments) are very selective targeting agents. A wide variety of antibody based therapeutics have been developed in the last 2 decades. Antibody imaging offers the potential of: - Stratifying patients that may benefit from antibody therapy - Monitoring the course of therapy - Paving the way for next generation targeted radiotherapeutics Chemistry Half life Decay Properties Availability Purity Standard PET Isotopes Radiometals 14 N(p,α) 11 C t ½ = 20.3 min. 18 O(p,n) 18 F t ½ = min. 16 O(p,α) 13 N t ½ = 9.97 min Often have longer half-lives to probe longer biological processes. Variety of half-lives and decay characteristics available (can be used for imaging or therapy). Co-ordination chemistry varies, thus stable chelates are the key. 14 N(d,n) 15 O t ½ = 2.0 min Toolbox: Chart of the Nuclides Radiometals? ~3000 known isotopes p Second row: n 3
4 Current Research Isotope production and separation chemistry Radiochemistry for new imaging agents Characterization of new radiopharmaceuticals Translation into clinical trials Cyclotron Production of Radionuclides Cyclotrons (Washington University) JSW 16/8 RDS 111 Japan Steel Works CTI/Siemens 16 MeV protons; 8 MeV deuterons 11 MeV protons 50 μa (total) 80 μa (total) 1extraction port 2 extraction port Liquid, and gas targets Liquid and gas targets Cyclotrons (Washington University) CS 15 The Cyclotron Corporation 15 MeV protons 50 μa (total) 1 extraction port, 3 beamlines Solid, liquid, and gas targets Closed: Opened: Beam Magnets: Cyclotrons (Washington University) TR 19/9 Advanced Cyclotron Systems, Inc. (ACSI) 19 MeV protons; 9 MeV deuterons variable energy 200 μa (total) 2 extraction ports Solid, liquid, and gas targets 4 beamline stations Cyclotrons (University of Alabama at Birmingham) TR 24 Advanced Cyclotron Systems, Inc. (ACSI) MeV protons; variable energy 300 μa (total) 2 extraction ports Solid, liquid, and gas targets 4 beamlines Installed: 22 Feb
5 PET Radiometals Zirconium- Isotope Half Life Target Material 52 Mn 5.6 d 52 Cr 55 Co 17.5 h 58 Ni 64 Cu 12.7 h 64 Ni 86 Y 14.7 h 86 Sr Zr 3.27 d Y Half-life of 3.27 d well suited for study of pharmacokinetics of antibodies (achieve optimal biodistribution ~4-5 d) Scouting in preparation for immunotherapy, confirming tumor targeting, and estimating dosimetry Generally inert to biological systems Decay properties EC = 76.6% + = 22.3% R ave. ( + )= 1.18 mm Zr- production and purification Scale Up and Automated Separation Y(p,n) Zr Purified by hydroxamate resin Modified Accell Plus resin (Waters) Weak cation exchange resin Accell resin Hydroxamate resin Wooten et al. App Sci 2013 EGFR in Human Carcinogenesis EGFR activation mediates multiple processes Adapted from: Ciardiello F, et al. N Engl J Med. 2008;358:
6 EGFR Expression in Solid Tumors EGFR-Targeted Monoclonal Antibodies Cetuximab Human-mouse chimeric IgG 1 mab Approved for advanced colon cancer and head and neck cancer Panitumumab Fully humanized IgG 2 mab Approved for advanced colon cancer EGFR Expression on Different Cancer Cell Lines : Flow Cytometry Data Labeling of Panitumumab with Zr (a) mab conjugation to DFO-Bz-NCS ~98% ~44% A431(lung ) 0% HCT116 (colorectal) 0% (b) Radiolabeling of DFO-Bz-NCS-Panitumumab T47D (breast ) MDA-MB-435(breast ) Imaging EGFR Expression with [ Zr]DFO-Bn-NCS-Panitumumab at 24 h Post Injection Imaging EGFR Expression with [ Zr]DFO-Bn-NCS-Panitumumab at 120 h Post Injection Tumor Tumor A431 HCT116 MDA-MB435 T47D A431 HCT116 MDA-MB435 T47D 6
7 SUV max of Tumors SUV max h 5 120h A431 HCT116 T47D MDA-MB435 Specificity of [ Zr]DFO-Bn-NCS-Panitumumab HCT h 120 h HCT116 + block HCT116 HCT116 + block Immunofluorescent Staining of Tumors Human Epidermal Growth Factor Receptor 2 (HER2) A431 HCT116 MDA-MB435 T47D Transmembrane receptor No known natural ligands Amplified in approximately 20 % of invasive breast cancers Associated with increased tumor aggressiveness, resistance to therapies, and increased mortality Anti-HER2 Antibodies Trastuzumab Binds to domain IV Suppresses HER2 signaling activity Pertuzumab Binds to domain II Inhibit HER2 dimerization by sterically preventing HER2 pairing with other growth factor receptors Marks tumor cells for immunological attack through antibody-dependent cell-mediated cytotoxicity Trastuzumab) Clinically approved antibody Trastuzumab imaging agent may be useful for determining dosing strategies and for predicting response to Trastuzumab therapy /Antibody Drug Conjugates and T DM1 7
8 Zr: Conjugation and Labeling Zr-DFO-Trastuzumab (a) mab conjugation to DFO-Bz-NCS (b) Radiolabeling of DFO-Bz-NCS-Trastuzumab Her2+ Her2- Her2+ Her2-24 h 96 h Chang et al, Pharmaceuticals, 2012 Zr-DFO-Trastuzumab Imaging Metastasis Zr-DFO-Pertuzumab (5 days p.i) Bioluminescent Imaging Axial Chang et al, Pharmaceuticals, 2012 Sagittal Coronal MDA-MB-231 (negative) SKBR-3 BT-474 Imaging of Interactions of Trastuzumab and Pertuzumab Imaging of Interactions of Trastuzumab and Pertuzumab Both Zr-Trastuzumab and Zr-Pertuzumab have excellent imaging properties for assessing HER2 status in vivo in preclinical models. Both Zr-Trastuzumab and Zr-Pertuzumab can be blocked by administering excess amount of the respective native antibody. The administration of excess amounts of Trastuzumab causes a significant increase in the uptake of Zr-Pertuzumab which may have implications for the combined use of these agents in chemotherapy. These finding are in agreement with a previous in silico study (Fuentes et al Breast Cancer Research. 2011;13: R54) Marquez et al, Mol Pharmaceutics, 11(11): , 2014 Marquez et al, Mol Pharmaceutics, 11(11): ,
9 Zr-DFO-Trastuzumab Washington University Clinical Trial Assessment of HER2 Receptors in Breast Carcinoma by Positron Emission Tomography (PET) Using Zr- Trastuzumab PI: Farrokh Dehdashti Arms Experimental: Cohort 1 Zr-Trastuzumab Human Dosimetry and Safety Experimental: Cohort 2: Lesion Detection and Safety HER2 Positive Lesion Detection and Safety Assigned Interventions Drug: Zr-Trastuzumab Human Dosimetry and Safety PET Imaging following administration of Zr labeled Trastuzumab for calculation of human dosimetry and overall safety Drug: HER2 Positive Lesion Detection and Safety Detection of HER2 Positive Breast Cancer with Zr Labeled Trastuzumab and PET imaging Drug: Zr-Trastuzumab Human Dosimetry and Safety PET Imaging following administration of Zr labeled Trastuzumab for calculation of human dosimetry and overall safety Drug: HER2 Positive Lesion Detection and Safety Detection of HER2 Positive Breast Cancer with Zr Labeled Trastuzumab and PET imaging Zr-DFO-Trastuzumab Washington University Clinical Trial IND submitted by Wash U All dosimetry and QC methodology developed in house (including immunoreactivity) Toxicity conducted externally Capable of up to 3 patients per batch and multiple batches per week Conjugation and radiochemistry conducted as per USP <823> Radiopharmaceuticals for Positron Emission Tomography (PET) Compounding, Investigational, and Research Uses Zr-DFO-Trastuzumab Dose Preparation Zr-DFO-Trastuzumab Quality Control Pre Release QC Samples Post Release Prepare LFH Combine DFO- Trastuzumab and Neutralized Zr- Oxalate and Incubate Prepare Final Product Vial and Spin Column Add DTPA and Purify Product via Spin Column Sterile Filter Final Product and Dilute Sample Withdraw QC Samples, test filter membrane, and begin QC Visual, ph, strength Endotoxin Testing FPLC Analysis for Aggregates Sterility Testing Radiochemical Purity Testing (itlc) Immunoreactivity Testing (Lindmo Assay) Zr-Trastuzumab Clinical Trial: Day 2 Zr-Trastuzumab Clinical Trial: Day 5 9
10 Other Sites: MSKCC Other Sites: MSKCC Other Sites: MSKCC, Zr- DFO-J591 Other Sites: MSKCC 56y/o male Dx adenocarcinoma prostate Gleason 9 (3 years prior) Prior treatment Lupron Brachytherapy and XRT Casodex PSMA directed T cell plus Cyclophosphamide (ongoing) Castration Resistant Sites of disease Bone Nodal Zr DFO J mci Imaged 3h, 1d, 3d, 7d Pharmacokinetics Summary Radiolabeled antibodies can play an important role in precision medicine. These agents may be used for Stratifying patients that may benefit from antibody therapy Monitoring the course of therapy Paving the way for next generation of targeted radiotherapeutics Development and increased use of these agents will require collaborations between chemists, biologists, physicians and pharmacists. Acknowledgments and Funding WUSM Lapi Lab members Bernadette Marquez, Brian Wright, Jennifer Burkemper, Tolu Aweda, Nilantha Bandara, Alex Zheleznyak, Xingyu Nie, Andrew (Lake) Wooten, Nora Goscinski, Vernal Richards, Tara Mastren, Tayo Ikotun, Albert Chang Isotope Production Team, WUSM Tom Voller, Evelyn Madrid, Efrem Mebrahtu, Paul Eisenbeis, Bill Margenau, Pat Margenau, Luke Lawrence Greg Gaehle and Sally Schwarz, WUSM Farrokh Dehdashti, Adel Tabchy, Ron Bose and Reiko Oyama, WUSM Jason Lewis MSKCC Financial Support from Department of Energy and the NIH 10
11 Self-Assessment Question 1 Imaging with radiolabeled antibodies could potentially be used for: A. Stratifying patients who might benefit from antibody therapy B. Monitoring the course of therapy C. Paving the way for the next generation of targeted therapeutics D. All of the above Self-Assessment Question 2 What chelator is typically used for Zr chemistry? A. EDTA B. NOTA C. DFO D. DTPA Self-Assessment Question 3 The half life of Zr is A. 110 minutes B. 3.3 days C. 8 days D. 60 days Self-Assessment Question 4 Pre release quality control criteria for Zr antibody includes A. Immunoreactivity B. Sterility C. Ethanol content D. Endotoxin Self-Assessment Question 5 Imaging of HER2 status in breast cancer patients may provide insight into A. Determining which patents may benefit from antibody therapy B. Tumor metabolic function C. Determining which patients may be resistant to radiotherapy D. Tumor oxygen tension 11
NIH Public Access Author Manuscript Biochem Pharmacol (Los Angel). Author manuscript; available in PMC 2014 October 24.
NIH Public Access Author Manuscript Published in final edited form as: Biochem Pharmacol (Los Angel). ; 1:. doi:10.4172/2167-0501.1000e128. Application of Positron Emission Tomography in Drug Development
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