1. Evolution of a “System” for Surgical Treatment of Adenocarcinomas
Charles L. Hitchcock, M.D., Ph.D.
Emeritus Faculty, Department of Pathology
The Ohio State University College of Medicine
Columbus, OH, USA

2. Clinicians Engineers Basic Scientists Cancer Surgeons Imaging ME/AE
Nuc Med
Pathology
Surgical Oncology
Engineers
ME/AE
EE/CE
BME
The James Cancer Hospital
Wexner Medical Center
Basic Scientists
Chemistry
Radiology
Pathology
Biostats

3. Monoclonal Antibody Fragments
The System - Today
Patient
Clinical Management
Surgery
Pathology
Medical Oncology
Radiation Oncology
Nuclear Medicine
Molecular Probes
Small Molecules
Peptides
Monoclonal Antibody Fragments
Molecular Imaging
& Detection Devices
Scanners
Gamma Camera
Gamma Probes
LFOVGC
The system today
Case of gastrinoma
Images
Results
To understand where we want top go you have to understand our hhistory

4. The System – Proof of Concept
Molecular Imaging
Detection Devices
Real Time
Intraoperative Imaging
Patient
17-year-old female
Serum gastrin
2,620 pg/mL
Spleen
Kidney
Tumors
LFOVGC
The system today
Case of gastrinoma
Images
Results
To understand where we want top go you have to understand our hhistory
Molecular Probe
In111–pentetreotide
NC Hall et al. JACS 2015; 221:

5. Monoclonal Antibody Fragments
The System - Yesterday
Patient
Clinical Management
Surgery
Pathology
Medical Oncology
Rad Onc
Nuclear
Medicine
Molecular Probes
Small Molecules
Peptides
Monoclonal Antibody Fragments
Molecular Imaging
& Detection Devices
Scanners
Gamma Camera
Gamma Probes
LFOVGC
Patients
Colorectal Carcinomas
Molecular Probe
125I-Murine CC49
anti-TAG-72
Imaging – CT Only
Detection Devices
Hand-held gamma detector probe
Clinical Management
Chemo

6. Why TAG-72? Sialyl-Tn linked mucin Associated with carcinomas
Signet Ring Carcinoma
Sialyl-Tn linked mucin
Associated with carcinomas
Breast >60% (~120,000/yr)
Lung ~ 80% (72,000/yr)
Prostate ~80% (168,000/yr)
Colorectal ~85% (115,000/yr)
Endometrium >90% (~27,000/yr)
Pancreas ~90% (~42,000/yr)
Sialyl-Tn
Mucin

7. The System - Yesterday Patients Molecular Probe Imaging – CT Only
Colorectal Carcinomas
Molecular Probe
Target TAG-72
125I-Murine CC49
Imaging – CT Only
Detection Devices
Hand held gamma detector
Clinical Management
Chemo

8. The System - Yesterday Patients Molecular Probe Imaging – CT Only
AJCC Stage
Patients
Molecular Probe
125I-anti TAG-72 (Murine CC49)
Imaging – CT Only
Detection Devices
Hand held gamma detector
Clinical Management
Chemo
TAG (+)
TAG (-)
TAG-72 Status
@ Closing

9. Monoclonal Antibody Fragments
The System - Tomorrow
Clinical Management
Surgery
Pathology
Medical Oncology
Radiation Oncology
Nuclear Medicine
Molecular Imaging
& Detection Devices
Scanners
Gamma Camera
Gamma Probes
Patient
The system today
Case of gastrinoma
Images
Results
To understand where we want top go you have to understand our hhistory
LFOVGC
Molecular Probes
Monoclonal Antibody Fragments

10. The System – Tomorrow: Molecular Probes
B72.3, CC49, CC83
ENL210
Anti-TAG 72 Monoclonal Antibody
Whole Antibody
150kD
ScFv, Diabody, Triabody, Tetrabody
~25kD
Humanized No
Yes
Biologic Half-life
2-3 days
2-3 hours
Tumor Localization
80%
>90%
Isotope
125I (T½ 60 days)
123I (T½ 13 hours)
Decay Storage
2 Years
5 days
Tumor : Background 24 hours
1 : 1
1 : 29
Preoperative Imaging
Intraoperative Imaging
Intraoperative Hand-Held Gamma Probe

11. The System – Evolution of Anti-TAG-72 MoAbs
ENL210 is a 26 kD polypeptide, fully humanized antibody fragment
Binds very tightly with a 3.6 nM apparent KD, ensuring low doses
Highly stable molecule, apparent melting temperature of 66 ºC
Stable to aggregation and degradation for >3 mo. at 4 ºC
The linker is optimized to produce a stable, reproducible mixture of diabody, triabody and tetrabody
About 95% of material clears from blood in 24 h, providing plenty of time for tumor binding and clear images in about 1 day
ENL210

12. The System – Tomorrow: Imaging and Detection
Pre-operative CT Imaging
Pre-operative SPECT/CT Imaging
Day of
Surgery
Radiology
Suite
123I-ENL210
Real Time Intraoperative Imaging and Detection
Operating
Room

13. The System – Tomorrow: Imaging and Detection

14. The System: Tomorrow Did you get it all? Is the therapy working?
Colorectal Carcinomas
Colonoscopy
CT scan (Primarily image anatomical
differences in tissues; 50 % accurate
FDG/PET/CT is non-specific and 50-60% accurate
Problem
For best results for the patient:
Outcome
Therapeutic decision making
Ultimately survival
Why change from
current management?
Solution
If images show too much tumor… systemic therapy. Started and followed with more images to assess effectiveness of therapy.
Preoperative Imaging
Molecular Imaging
123I or 124I-ENL210
Appointment with medical
oncologist: Systemic therapy
Appointment with surgeon
and review scans
2,3 weeks between appointment and
surgery.
Did you get it all?
Is the therapy working?
How am I doing?
If image shows tumor
Progression …
consider phase 1
131I-ENL210 clinical trial
Intraoperative imaging
and probing
with 123I-ENL210
Inject 123I-ENL210
18-36 hrs before surgery.
Follow therapeutic effectiveness
With Molecular Imaging
with 123Ior 124I-ENL210

15. THANK YOU