KW seminar: Molecular imaging

Question 1

What is molecular imaging?

Answer 1

Molecular imaging encompasses a variety of imaging techniques that rely on the use of exogenously added specific probes (tracers/contrast agents) to target and detect desired cellular and molecular processes in a living organism.

Question 2

Very roughly, what different techniques are there?

Answer 2

• Ultrasound
• Photo acoustic microscopy
• Optical coherence tomography
• Magnetic force microscopy

Question 3

What is nuclear imaging?

Answer 3

Nuclear imaging is a method of producing images by detecting radiation from different parts of the body after a radioactive probe is given to the patient. The images are digitally generated on a computer and transferred to a nuclear medicine physician, who interprets the images to make a diagnosis

Also called “endoradiology”: because (it records radiation emitting from within the body rather than radiation that is generated by external sources like X-rays. In addition, nuclear medicine scans differ from radiology, as the emphasis is not on imaging anatomy, but on the function.

Question 4

What are the two most common forms of nuclear imaging?

Answer 4

Single photon emission computed tomography (SPECT) and positron emission tomography (PET)

Question 5

What is optical imaging?

Answer 5

Medical optical imaging is the use of light as an investigational imaging technique for medical applications. The probe that could be used for this is fluorescent dye

Question 6

What are some examples of optical imaging?

Answer 6

Optical microscopy, spectroscopy, endoscopy, scanning laser ophthalmoscopy, laser Doppler imaging, and optical coherence tomography.

The lecturer doesn’t name this, but I think he means microscopy when referring to optical imaging. All the other forms you do not have to study

Question 7

Explain what the sensitivity, resolution and depth is of nuclear imaging (probe: radionuclide)

Answer 7

Sensitivity: high

Resolution: moderate

Depth: whole body

Question 8

Explain what the sensitivity, resolution and depth is of optical imaging (probe: fluorescent dye)

Answer 8

Sensitivity: high

Resolutation: high

Depth: superficial

Question 9

Explain what the sensitivity, resolution and depth is of MRI imaging (probe: paramagnetic agent)

Answer 9

Sensitivity: poor

Resolution: high

Depth: whole body

Question 10

For an overview and comparison of the different molecular imaging, see this figure

Answer 10

Okay

Question 11

What two molecular imaging are the best options for molecular imaging, due to picomolar sensitivity?

Answer 11

Nuclear and optical imaging (MRI has a poor sensitivity)

Question 12

What two forms of molecular imaging are best for examining the whole body?

Answer 12

Nuclear and MRI imaging (optical imaging is very superficial, and you need a thin slice of tissue to study under the microscope)

Question 13

What probe is used in a PET-scan?

Answer 13

A sugar, called F-18 FDG

Question 14

What shift is seen in the clinic regarding imaging?

Answer 14

That, as we learn more about diseases, we are becoming more aware that this happens on cellular, and even genetic level. Therefore we are using molecular imaging nowadays more than e.g. X-rays

Question 15

Molecular imaging fills the gap between molecular ___, molecular ___ and molecular ___ ___

Answer 15

Molecular imaging fills the gap between molecular biology, molecular diagnosis and molecular targeted therapy

Question 16

Molecular imaging of targets and drugs. To keep the health care system affordable

Fill in:

In biology, ___ of disease as well as ___ drugs have to be understood better.

Drug design and development should become more efficient and cheaper: selection of ___ drugs at an early stage, with less patients in trials, showing the distinguished properties of the drug.

(Drug) treatment should become more ____.

Answer 16

In biology, targets of disease as well as targeted drugs have to be understood better.

Drug design and development should become more efficient and cheaper: selection of high potential drugs at an early stage, with less patients in trials, showing the distinguished properties of the drug.

(Drug) treatment should become more “personalized/precise”.

Question 17

True/false: Drug development is too expensive

Answer 17

True

Development costs of drug to market: > 1 billion dollar

Question 18

Drug development is not efficient enough. About 65% of the trials fail at a certain phase. Which phase is this?

Answer 18

Phase II of clinical trials

Question 19

Drug development is not efficient enough. How many % of drugs in clinical devleopment reach the market?

Answer 19

About 10% of drugs in clinical development reaches the market

Question 20

We’ve seen that 10% of the drugs in clinical trials reach the market. However these drugs are not effective enough. Why?

Answer 20

Because often only 40% of the patients benefit from the drug. Imagine that a drug sales worldwide yearly ~1000 billion euro’s. This means that 600 billion is spent in vain because the patients do not benefit

Question 21

There has been a change in the categories of drugs (size). What is this change?

Answer 21

From small chemical molecules to a diversity of biologicals.

Question 22

Why is there a change from small chemical molecules to a diversity of biologicals?

Answer 22

Becuase biologicals have a much longer half-time (e.g. peptides hav a half-life of 2 hours before they are destroyed by the liver, monoclonal antibodies 120+ hours)

Question 23

What are the characteristics of next generation targeted biologicals?

Answer 23

More potent, multiple specificities and (immune) functions

Question 24

What are some examples of next generation targeted biologicals?

For illustration

Answer 24

• Antibody drug conjugates (ADCs)
• Immune checkpoint inhibiting antibodies (ICIs)
• Fusion antibodies, e.g. immunocytokines
• Bi- and multispecific antibodies
• Antibody fragments, antibody-like scaffolds
• Polynucleotides
• Nanoparticles
• Cells

Question 25

Where is the UMC imaging center?

Answer 25

At the zuidas, on the VU campus

Question 26

At what three ‘stages’ of the care cycle during the treatment of a cancer patient is imaging used and why?

Answer 26

1. Diagnose/stratification: what/where/how is the disease
2. Image-guided therapy: Is the disease accurately targeted?
   
   • Surgery, radiotherapy, chemotherapy, immunotherapy and nanotherapy
3. Response monitoring: is the treatment effective?

Question 27

Probes and positron emitters for PET imaging. Fill in:

• Fast kinetics targeting probes are long/short-lived radionuclides
• Slow kinetics targeting probes are long/short-lived radionuclides

Answer 27

• Fast kinetics targeting probes are short-lived radionuclides
• Slow kinetics targeting probes are long-lived radionuclides

Question 28

What is the potential impact of drug imaging?

Answer 28

• Assessment of expression and accessibility of target (also in e.g. brain).
• Assessment of pharmacokinetics and biodistribution of drug.
• Whole body, non-invasive, quantitative and longitudinal.
• Confirmation of selective disease targeting – anticipate toxicity.
• Optimization of drug dose: avoiding “sinks”, homogeneous targeting.
• Identification of patients group with highest chance of benefit.
• Individualization of therapy (companion – complementary diagnostics).
• Mechanism of action: showing distinguished properties of a drug.

Question 29

How can 89-Zr labeling be used in the clinic?

Answer 29

It can be used for drug targeting. For example, you bind 89ZR to rituximab so that it binds specifically to tumor cells

Question 30

Can 89Zr-trastuzumab also be used to detect metastasis?

Answer 30

Yes, although not seen in the PET scan (left image), the 89-Zr-trastuzumab did show metastasis in the body (middle figure), which were later shown atanomicall (right figure)

Question 31

Since trastuzumab is very selective, and has shown to point out metastasis not only in mice but also in humans (see figure). How can this further be usedin the clinic?

Answer 31

It allows the use as an Antibody-drug conjugate (ADC). You can bind a drug to the marker, so that the drug only binds to the tumor

Question 32

What are the advantages of using both radiochemistry and imaging in ADC development?

Answer 32

• controlled coupling
• unimpaired MAb integrity
• and antigen binding
• stable in vitro and in vivo
• optimal tumor targeting

Question 33

How can platinum (Lx) be used in the clinic?

Answer 33

As a 2-sided adhesive, the (toxic) drug can bind on one side, and an antibody on the other

This is called linker technology

Question 34

What efficacy does the linker technology show?

Answer 34

Improved efficacy

Question 35

What did we learn from alleviating PD1/PD-L1 mediated inhibition?

As an example

Answer 35

We understood the immune system

Question 36

What results were found with use of molecular imaging with targeting reumatoid artritis?

As an example

Answer 36

With inhibition of 89Zr-rituximab (CD20/B cells), the disease could clearly be shown and targeted at the same time

Question 37

How could you evade the problems of a drug in a deep brain tumor, which has a impossible location to operate, and many drugs don’t pass the blood-brain-barrier?

Not study material

Answer 37

By using a intra-arterial (IA) injection with a blood-brain-barrier opening

See the red bars which are much higher than the blue/grey

Question 38

Thus with use of the PET scan, 89Zr-antibody gives access to the brain. In what other diseases besides brain tumors could this treatment be developed?

Not study material

Answer 38

All brain diseases, Alzheimer’s, Parkinson’s, MS