labeled antibodies for molecular...

Labeled antibodies formolecular imaging

Annelies Jorritsma, PharmD, PhD

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Disclosure

(potential) Conflict of Interest None

Overview

• Antibodies

• Molecular imaging

─ Nuclear tracers

─ Optical tracers

• Application

─ Drug development

─ Therapy

─ Image-guided surgery

• Antibody-like proteins

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Antibodies & targets

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Antibodies with marketing authorization

Kaplon MABS 2019/2018

Reichert MABS 2017/2016/2012

www.pei.de, www.actip.org

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Antibodies in first-in-human studies

Figure from: Kaplon & Reichert, MABS 2019

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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?

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Early drug development trials

collection of PK data tumor characterization via biopsy

In vivo visualization of biomarkers using molecular tracers

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Antibodies as targeting moiety in molecular imaging

Molecular imaging

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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

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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

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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

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Production of optical tracers

mAb dye labeled mAb

800CW800CW

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Imaging of optical tracers

Endoscope

Procedure

• I.v. injection of 4.5 mg

• Imaging on day 2-3 post tracer injection

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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

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Molecular imaging: pros and cons

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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

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Drug development Therapy Image guided surgery

• Biodistribution

• Dose finding

• Tumor targeting

• Staging

• Patient selection

• Treatment response

• Visualization of tumor/metastasis

• Assess tumor margin


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• Biodistribution

• Dose finding

• Tumor targeting

• Staging





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

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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

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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

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Bensch, Clin Cancer Res 2017

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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


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• Biodistribution

• Dose finding

• Tumor targeting

• Staging





Gaykema, J Clin Oncol, 2012

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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

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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

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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

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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


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• Staging





• Biodistribution

• Dose finding

• Tumor targeting

Nagengast, Gut, 2019

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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

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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


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• Biodistribution

• Dose finding

• Tumor targeting

• Staging





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Engineered antibodies and fragments

Drawbacks to antibody imaging

• Large size > slow clearance from non target tissue

• Large size > poor penetration into target tissues

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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

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Imaging with VHHs

• 15 kDa VHH

• directed against HER2

• Labeled with IRDye 800CW

Kijanka EJNMMI 2013

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Validation studies are needed

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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

www.umcg.nl

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[email protected]

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