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Labeled antibodies formolecular imaging
Annelies Jorritsma, PharmD, PhD
2
Disclosure
(potential) Conflict of Interest None
Overview
• Antibodies
• Molecular imaging
─ Nuclear tracers
─ Optical tracers
• Application
─ Drug development
─ Therapy
─ Image-guided surgery
• Antibody-like proteins
3
Antibodies & targets
4
Antibodies with marketing authorization
Kaplon MABS 2019/2018
Reichert MABS 2017/2016/2012
www.pei.de, www.actip.org
5
Antibodies in first-in-human studies
Figure from: Kaplon & Reichert, MABS 2019
6
7
Issues
• How to select patients for the right treatment?
• How to decide early whether the patient
responds or not?
• Does the drug reach its target?
• How to dose the new drugs?
• Role of heterogeneity?
8
Early drug development trials
collection of PK data tumor characterization via biopsy
In vivo visualization of biomarkers using molecular tracers
9
Antibodies as targeting moiety in molecular imaging
Molecular imaging
10
MAb
Nuclear Optical
89Zirconium
• Positron emitter
• T1/2 = 72 hours
• Residualizing
IRDye 800CW
• Fluorescent dye
• Near-infrared: abs 774nm, ext 789nm
Production of nuclear tracers
11
Imaging of nuclear tracers
Procedure
• I.v. injection of 37 MBq
• Imaging on day 2, 4 and 7 post tracer injection
• ~15 bed positions
• 5-10 min/pos
12
UMCG 89Zr tracer panel
Tracer Target Tumor type Ref
89Zr-bevacizumab VEGF
Von Hippel Lindau Oosting J Nucl Med 2016
Metastatic RCC Oosting J Nucl Med 2015
Breast Cancer (HSP90 inh) Gaykema Clin Cancer Res 2014
Primary Breast Cancer Gaykema J Nucl Med 2013
Renal Cell Carcinoma Van Es J Nucl Med 2017
89Zr-trastuzumab Her2
Breast Cancer (TDM-1) Gebhart Ann Oncol 2016
Breast Cancer (HSP90 inh) Gaykema Clin Cancer Res 2014
Breast Cancer (clinical dilemma) Gaykema JCO 2012
Metastatic Breast Cancer Dijkers Clin Pharmacol Ther 2010
Breast Cancer Bensch EJNMMI 2018
89Zr-lumretuzumab Her3 Her3+ solid tumors Bensch Clin Cancer Res 2017
89Zr-MMOT0530A Mesothelin Pancreatic/Ovarian Cancer Lamberts Clin Cancer Res 2016
89Zr-fresolimumab TGF-βR Glioma Den Hollander J Nucl Med 2015
89Zr-AMG211 CEA Gastrointestinal adenocarcinoma Moek Clin Cancer Res 2019
89Zr-pembrolizumab PD-1 Melanoma, NSCLC Ongoing
89Zr-atezolizumab PD-L1 Bladder, NSCLC, Breast Bensch Nat Med 2018
13
Production of optical tracers
mAb dye labeled mAb
800CW800CW
14
Imaging of optical tracers
Endoscope
Procedure
• I.v. injection of 4.5 mg
• Imaging on day 2-3 post tracer injection
15
UMCG 800CW tracer panel
Tracer Target Tumor type Ref
Bevacizumab-800CW VEGF
Breast Cancer Lamberts Clin Cancer Res 2017
Koller Nat Commun 2018
FAP/Colorectal adenoma Harmans Theranostics 2018
Rectal Cancer Tjalma Gut 2019
De Jongh J Nucl Med 2019
Peritoneal Carcinomatosis Harlaar Lancet Gast Hepat 2016
Esophageal Cancer Nagengast Gut 2019
Cetuximab-800CW EGFRHead and Neck Cancer Ongoing
Oral Cancer Ongoing
16
Molecular imaging: pros and cons
17
Nuclear Optical
• Whole body
• Quantitative
• Relatively low resolution
• High cost
• Complex infrastructure
Pro
Con
• High resolution
• High sensitivity
• No radioactive load
• Limited penetration depth
• No whole body imaging
• Less quantitative
Applications of molecular imaging
18
Drug development Therapy Image guided surgery
• Biodistribution
• Dose finding
• Tumor targeting
• Staging
• Patient selection
• Treatment response
• Visualization of tumor/metastasis
• Assess tumor margin
Applications of molecular imaging
19
Drug development Therapy Image guided surgery
• Biodistribution
• Dose finding
• Tumor targeting
• Staging
• Patient selection
• Treatment response
• Visualization of tumor/metastasis
• Assess tumor margin
Molecular imaging in drug development89Zr-MMOT0530A (anti-mesothelin)
Biodistribution
• Phase I study with antibody-drug conjugate DMOT4039A
• 37 MBq 89Zr-MMOT0530A with 10 mg unlabeled MMOT0530A
• PET-scan on day 2 (blue), 4 (green) and 7 (yellow)
• Organ distribution showed high uptake in the circulation, liver, kidneys, spleen and intestine
• Biodistribution was largely comparable to that of other labeled mAbs
• Liver uptake rises over time, suggesting liver as potential site of toxicity
Lamberts, Clin Canc Res, 2016
Bensch, Theranostics, 2018
20
Molecular imaging in drug development89Zr-MMOT0530A (anti-mesothelin)
Tumor targeting
• Tumor tracer uptake occurred in 37 lesions with mean SUVmax of 13.1 (± 7.5) on PET
4 days postinjection─ pancreatic cancer lesions (N=17):
SUVmax 11.5 (± 7.5)
─ ovarian cancer lesions (N=20):
SUVmax 14.5 (± 8.7)
• Heterogeneous uptake between and within patients
Lamberts, Clin Canc Res, 2016
21
Molecular imaging in drug development89Zr-lumretuzumab (anti-Her3)
Tumor targeting
• Patients with HER3+ tumors (a.o. rectal, colon, ovarian, HNC, breast)
• 37 MBq 89Zr-lumretuzumab with 100 mg unlabeled lumretuzumab
• PETscan 4 days after injection
• Tracer uptake in lesions across the body (apart from liver)
• Heterogeneous uptake between and within patients
Bensch, Clin Cancer Res 2017
22
Bensch, Clin Cancer Res 2017
23
Molecular imaging in drug development89Zr-lumretuzumab (anti-Her3)
Dose finding
• 89Zr-lumretuzumab PET scan before and during treatment with lumretuzumab
• decreased tumor uptake already after 400 mg
• No clear evidence of tumor saturation since no plateau
Applications of molecular imaging
24
Drug development Therapy Image guided surgery
• Biodistribution
• Dose finding
• Tumor targeting
• Staging
• Patient selection
• Treatment response
• Visualization of tumor/metastasis
• Assess tumor margin
Gaykema, J Clin Oncol, 2012
25
Molecular imaging in therapy
Staging
Assessment of HER2 status
• 34-year-old woman with two primary breast cancers:
─ ER-, PgR-, and HER2-
─ ER+, PgR-, HER+
• Treatment by surgery and chemotherapy (including trastuzumab)
• 2 years later large mediastinalmass detected on CT
• 89Zr-trastuzumab scan to determine which primary tumor had metastasized
• HER+ lesions > treatment with trastuzumab in combination with standard chemotherapy
Bensch, Nature Med, 2019
26
Molecular imaging in therapy
Patient selection
• 89Zr-atezolizumab PET scan followed by atezolizumabtreatment
• Tracer uptake high in lymphoid tissue and site of inflammation
• Tracer uptake high but heterogeneous in tumors
Bensch, Nature Med, 2019
27
Molecular imaging in therapy
Patient selection
• 89Zr-atezolizumab uptake correlated with responses
Top: correlation with SUVmax
SUVmax ≥ 9.0
SUVmax < 9.0
Middle: correlation with PDL1 ICH
SP263 positive
SP263 negative
Bottom: correlation with PDL1 ICH
SP142 IHC 1 or 2
SP142 IHC 0
Tjalma, Gut, 2019
29
Molecular imaging in therapy
Treatment responseEvaluate neoadjuvanttreatment
• Locally advanced rectal cancer treated with neoadjuvant chemo-radiotherapy followed by surgery
• However, 15-27% of patients no residual cancer
• Bevacizumab-800CW imaging to identify clinical complete response before surgery
• Improved prediction of final pathology results in 4/25 patients compared with standard MRI and white light endoscopy
Applications of molecular imaging
30
Drug development Therapy Image guided surgery
• Staging
• Patient selection
• Treatment response
• Visualization of tumor/metastasis
• Assess tumor margin
• Biodistribution
• Dose finding
• Tumor targeting
Nagengast, Gut, 2019
31
Image guided surgery
Visualization of lesions
• Patients with Barrett’s oesophagus > risk of eosophagal adenocarcinoma
• Systemic and topical administration of Bevacizumab-800CW
• Enhancement of detection rate: 25% overall, 33% topical
Koller, Nature Commun, 2018
32
Image guided surgery
Margin assessment
• Increasing doses of bevacizumab-800CW (4.5, 10, 50 and 100 mg)
• Intraoperative imaging before and after excision
• Retrospective correlation with histopathology
• 8/26 tumor positive surgical margin:
─ none detected by current surgical practice
─ 7/8 detected by fluorescence
• 18/26 tumor negative surgical margin:
─ 16/18 no fluorescence
─ 2/18 fluorescence but also in surrounding healthy tissue
Intraoperative fresh specimen Intraoperative fresh specimen
Surgical margin
tumor positive
Surgical margin
tumor negative
Total
Fluorescence signals
in cavity positive
7 2 9
Fluorescence signals
in cavity negative
1 16 17
Total 8 18 26
Applications of molecular imaging
33
Drug development Therapy Image guided surgery
• Biodistribution
• Dose finding
• Tumor targeting
• Staging
• Patient selection
• Treatment response
• Visualization of tumor/metastasis
• Assess tumor margin
34
Engineered antibodies and fragments
Drawbacks to antibody imaging
• Large size > slow clearance from non target tissue
• Large size > poor penetration into target tissues
35
Imaging with BiTEs
AMG 211
• 55 kDa bispecific T-cell engager (BiTE)
• directed against carcinoembryonic antigen (CEA) on tumor cells and CD3 on T-cells
• Labeled with 89Zr
• Visualization of whole body biodistribution and tumor targeting
Moek Clin Cancer Res 2019
36
Imaging with VHHs
• 15 kDa VHH
• directed against HER2
• Labeled with IRDye 800CW
Kijanka EJNMMI 2013
37
Validation studies are needed
38
Multidisciplinary effort
De Vries Nature Rev Clin Oncol 2018
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AcknowledgementsDepartment of Clinical Pharmacy and Pharmacology
Jos Kosterink
Marjolijn Lub-de Hooge
Derk Allersma
Daan Touw
Pauline Koopmans
Department of Medical Oncology
Liesbeth de Vries
Carolien Schroder
Geke Hospers
Linda Pot
Titia Lamberts
Frederike Bensch
Derk-Jan de Groot
Jourik Gietema
Department of Gasteroenterology
Dr. Wouter Nagengast
Matthijs Linssen
Wouter Hooghiemstra
Elmire Hartmans
Jolien Tjalma
Department of Surgery
Prof. Go van Dam
Marjory Koller
Steven de Jongh
Department of Nuclear Medicine and
Molecular Imaging
Rudi Dierkx
Adrienne Brouwers
Andor Glaudemans
Johan de Jong
Philip Elsinga
Erik de Vries
Dr. Gert Luurtsema
Acknowledgements