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Requirements for the Cure of Cancer: Formulating a Plan of Action. Workshop sponsored by the Van Andel Institute Jan. 10-11, 2007. FROM PRINCIPLES TO PRACTICE. SESSION VI(B) The development of technologies for targeting cells that express target patterns Arnold Glazier MD.

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Requirements for the cure of cancer formulating a plan of action

Requirements for the Cure of Cancer: Formulating a Plan of Action

Workshop sponsored by the Van Andel Institute

Jan. 10-11, 2007


From principles to practice

FROM PRINCIPLES TO PRACTICE Action

SESSION VI(B)

The development of technologies for targeting cells that express target patterns

Arnold Glazier MD




Ideal drug targeting
Ideal Drug Targeting Action

  • The tumor would act like a black hole for drug

  • All drug in the blood flow to the tumor would be irreversibly retained

  • No drug accumulation in non-target sites


Ideal drug targeting1
Ideal Drug Targeting Action

  • Based on a typical blood flow of 0.15 –0.6 ml/min/gm and 24 hours, maximum average tumor levels would be about 200-800 times the average blood level

  • The biological effects can be even orders of magnitude higher


Multiplicative increases in concentration can give exponential increases in effect
Multiplicative Increases in Concentration can give Exponential Increases in Effect

Surviving Cell Fraction versus Drug Concentration

Tirapazamine

Brown JM, Wouters BG.; . Cancer Res. 1999 Apr 1;59(7):1391


Examples of almost perfect targeting exist
Examples of Almost Perfect Targeting Exist Exponential Increases in Effect

  • Hormone/ receptor binding

  • Peanut allergy / anaphylactic shock

  • Nerve gas


Approaches towards ideal drug targeting
Approaches Towards Ideal Drug Targeting Exponential Increases in Effect

  • Specific, high affinity or irreversible binding

  • Slow “off rates” of drug from receptors

  • Administering the drugs at the lowest concentration needed to saturate “drug accessible” receptors

  • Decreasing nonspecific binding

  • Increasing the quantity of drug receptors (exponential PRTT)

  • Prolonging treatment time

Principles that can be applied towards achieving these goals are well known. (Multi-site binding, slow binding, covalent binding, etc..)


Major issues
Major Issues Exponential Increases in Effect

  • Chaotic and uneven blood flow

  • Limited drug penetration into tumors

  • Slow rates of drug diffusion

  • Episodic target pattern expression

  • On a given day only parts of a tumor will be drug accessible

The drugs need to be given continuously for prolonged periods of time. (6 months?)


The aim should be to deliver drug to drug accessible target patterns
The Aim Should be to Deliver Drug to “Drug Accessible” Target Patterns

  • The important pathology that sustains cancer occurs within a limited zone around blood vessels.

  • Areas close to blood vessels will be drug accessible.

  • Drug accessible cells will be killed, new layers of cancer cells will be exposed and killed over time in an “onion peeling effect”

  • Therapy needs to be sufficiently intense so that the rate of cell loss exceeds the rate of cell production


A Minor, Sustained Decrease in the Probability of Cancer Cell Survival can have Profound Effects

Data: Berman JJ, Moore GW; Anal Cell Pathol. 1992 Sep;4(5):359-68


Drugs targeted to a comprehensive set of target patterns will inhibit
Drugs Targeted to a Comprehensive Set of Target Patterns will Inhibit

  • Angiogenesis

  • Vasculogenic mimicry

  • Vascular co-option

This will achieve Dr. Folkman’s vision by effectively depriving tumor cells of new blood supply, constraining growth and allowing time for the “onion peeling” killing effect to work.


Non synchronous expression of target pattern elements
Non-synchronous Expression of Target Pattern Elements will Inhibit

Targeting specificity should be for

  • Invasiveness alone, or

  • Invasiveness and the potential for proliferation

Elements of these classes of target patterns are expressed concurrently.


Effector agents should be cell cycle independent

Effector Agents Should be Cell Cycle Independent will Inhibit

G2/mitotic-specific cyclin-B1 in colon cancer

http://www.proteinatlas.org/


The microenvironmental nature of invasiveness
The Microenvironmental Nature of Invasiveness will Inhibit

There is a requirement for approaches that generate a zone of anticancer activity in the local volume that surrounds target patterns


Major requirements
Major Requirements will Inhibit

The need for:

  • Pattern specificity

  • Signal amplification

  • Multiple, redundant mechanisms of cell killing or inactivation

  • Prolonged therapy

  • The ability to simultaneously give multiple drugs

  • Chemical stability

  • Lack of antigenicity

  • Modularity in design


The logic function of prtt drugs
The Logic Function of PRTT Drugs will Inhibit

A

B

C

Are all the elements of the pattern present ?

Yes

No

Kill Cell

Spare Cell

Specificity is for the pattern, not the individual elements.


1. Binding will Inhibit

2. Chemical bond formation

3. Breakage of chemical bonds

4. Catalysis of a reaction

5. Dissolution or precipitation

Medicinal Chemistry Boils Down To:


Modular building blocks
Modular Building Blocks will Inhibit

  • Targeting ligands

  • Triggers

  • Triggering agents

  • Effector agents

  • Linkers and scaffolds

  • Male and female adaptors

  • Masking groups

  • Molecular clocks

  • Intracellular transport ligand

  • Solubility modifiers

These components exist and are within the scope of current technology.


Targeting ligands
Targeting Ligands will Inhibit

Ligand Receptor Complex

Ligands are chemical groups that bind together like a lock and key to target receptors.


A urokinase selective ligand
A Urokinase Selective Ligand will Inhibit

Kd is in the low nanomolar range.

Tamura S Y., et al., Bioorganic Med Chem Lett,

10:983-987 (2000)


Triggers and triggering agents
Triggers and Triggering Agents will Inhibit

Trigger

Drug

molecule

Triggering

Agent

Chemically altered drug

Triggers are chemical groups then when acted upon by a triggering agent undergo a chemical change.

Enzymes and non-enzymes can serve as triggering agents.


Applications of triggers
Applications of Triggers will Inhibit

  • To turn on or off a chemical process

  • To activate a toxin

  • To inactivate a toxin

  • To unmask a ligand

  • To release a toxin


Effector agents
Effector Agents will Inhibit

  • Toxic agents that kill cells

  • Agents that irreversibly block the potential for cell proliferation

  • Agents that trigger an immune response

  • Agents that amplify a response


Linkers and scaffolds
Linkers and Scaffolds will Inhibit

Toxin

Trigger

Linkers

Scaffold

Targeting Ligands

Structural elements that provide the backbone of the drug


Cyclodextrins as scaffold
Cyclodextrins as Scaffold will Inhibit

Rigidity, multiple sites for linker attachment,

solubility, spatial separation of components,

low toxicity


Male and female adaptors
Male and Female Adaptors will Inhibit

The male and female parts bind specifically and tightly.

In the ideal case the binding is irreversible.


Masking groups

Triggering will Inhibit

Agent

Masked

Receptor

Unmasked

Receptor

Masking Groups

A masking group blocks a receptor.

A triggering agent can unmask the receptor.


Molecular clocks
Molecular Clocks will Inhibit

Trigger

Triggering

Agent

Chemical change

Molecular clocks provide an adjustable time delay between a triggering event and a chemical change.


Intracellular transport ligands
Intracellular Transport Ligands will Inhibit

Drug

Drug

Cell Receptor

Transport into Cell

Intracellular

Transport Ligand

Drug

Drug

Intracellular transporter groups can also work by physical, non-receptor mediated mechanisms.

Tumor Cell

Tumor Cell


A wide range of pattern targeting technologies can be developed by combining these modular building blocks in logical ways.


Prtt approaches
PRTT Approaches developed by combining these modular building blocks in logical ways.

  • Targeted delivery of a targeted agent

  • Targeted delivery of a trigger activated drug

  • Independently targeted synergistically toxic drugs

  • Multi-site binding

  • Exponential Pattern Recognition Targeting

  • Combinations of the above

  • Other


Targeted delivery of a targeted cytotoxic agent
Targeted Delivery of a Targeted Cytotoxic Agent developed by combining these modular building blocks in logical ways.


This method is the simplest and requires no new drug technology
This method is the simplest and requires developed by combining these modular building blocks in logical ways.no new drug technology


Targeted delivery of a targeted cytotoxic agent1
Targeted Delivery of a Targeted Cytotoxic Agent developed by combining these modular building blocks in logical ways.

Drug


The pattern is a surface receptor and intracellular target
The Pattern is a Surface Receptor and Intracellular Target developed by combining these modular building blocks in logical ways.

For cell killing both must be present


Targeted delivery of a targeted cytotoxic agent2
Targeted Delivery of a Targeted Cytotoxic Agent developed by combining these modular building blocks in logical ways.

The cytotoxic agent is toxic only if its target is present


The targeting receptor can also be in the tumor cell microenvironment

in developed by combining these modular building blocks in logical ways.

The Targeting Receptor Can Also be in the Tumor Cell Microenvironment


Targeted delivery of a trigger activated drug

Targeted Delivery of a Trigger Activated Drug developed by combining these modular building blocks in logical ways.


Targeted delivery of a trigger activated drug1
Targeted Delivery of a Trigger Activated Drug developed by combining these modular building blocks in logical ways.

Only cells that have both the target receptor and the triggering

enzyme will be killed.


A urokinase activated gmcsf receptor targeted diphtheria toxin
A Urokinase-Activated GMCSF Receptor Targeted Diphtheria Toxin

Trigger

Urokinase activates

Diphtheria toxin

Binds to GMCSF

Receptor on cells

The drug targets the pattern of urokinase and GMCSF receptor.

Ralph J. Abi-Habib, Shihui Liu, Thomas H. Bugge, Stephen H. Leppla, and Arthur E. Frankel; Blood, 1 October 2004, Vol. 104, No. 7, pp. 2143


Targeting the microenvironment
Targeting the Microenvironment Toxin

The drug is targeted to the microenvironment, released by the triggering enzyme, diffuses to the tumor cell and kills it.


Advantages of releasing a toxin into the tumor microenvironment
Advantages of Releasing a Toxin into the Tumor Microenvironment

  • Invasiveness is a property of both the cancer cell and its microenvironment

  • A zone of toxicity is created making it easier to kill all the cancer cells

Approaches that produce a zone of toxicity are strongly preferred.



Agent 1 Microenvironment

Agent 2

Paired, Independently Targeted

Synergistically Toxic Drugs


Individually, Agent 1 and Agent 2 are Nontoxic, But Toxic in Combination:

Agent 1

Agent 1

Agent 2

Agent 2

Tumor cell

Normal cell

Type B

Normal cell

Type A

No Toxicity Toxicity No Toxicity


Multi site binding

Multi-Site Binding Combination:


Multi site binding and pattern recognition
Multi-Site Binding and Pattern Recognition Combination:

Multi-site binding can give an enormous increase in the tightness of binding compared to single site binding


A Ten Billion Times Increase in Affinity due to Three Site Binding

Vancomycin

Tri-Vancomycin

Ala-Ala

Tri- Ala-Ala

Kd = 10 – 6

Kd = 10 –17

  • Rao J, Lahiri J, Isaacs L, Weis RM, Whitesides GM; Science 280:708-11 (1998)


Multi site binding1

Toxin Binding

Toxin

Tumor cell

Normal cell

Multi-Site Binding

No Binding

Tight Binding

At low concentrations the drug can bind tightly to cells with the target pattern without binding to cells that express only one element of the pattern


Advantages of multi site binding
Advantages of Multi-Site Binding Binding

  • Specificity for the pattern

  • Potency

  • Slow off rate

  • Immense reductions in the dose of drug required

  • Reductions in side effects


Exponential pattern recognition targeting

Exponential Pattern Recognition Targeting Binding

From one receptor create two, from two create four ….


Exponential Pattern Recognition Targeting Binding

Instead of consuming receptors, the targeted drug will in effect increase the target receptor density.

The more drug that is delivered, the more drug that can be delivered.



Components of exponential pattern recognition targeting
Components of Exponential Pattern Recognition Targeting and a triggering enzyme.

Masked Female Adapter

Toxin

Targeting Ligand

Male Ligand

1 2

The male and female parts bind with very high affinity.


The Mechanism of Exponential PRTT and a triggering enzyme.


Triggering enzymes unmask the female adaptor
Triggering Enzymes Unmask the Female Adaptor and a triggering enzyme.

  • Many enzymes that are over-expressed by tumors can be utilized

  • The triggering enzyme can also be independently targeted to tumor cells


Exponential pattern recognition targeting1
Exponential Pattern Recognition Targeting and a triggering enzyme.

Triggering enzyme

Tumor cell

Tumor cell

1.) Component 1 binds to cell receptors.

2.) Triggering enzyme(s) unmask female adapter.


Toxin and a triggering enzyme.

Toxin

Triggering enzyme

Tumor cell

Tumor cell

3) Component 2 binds to the unmasked female adaptor.

4) The triggering enzyme unmasks twice as many

new female adaptors.


Toxin and a triggering enzyme.

Toxin

Toxin

Toxin

Toxin

Tumor cell

Repetition of the cycle can deposit a large quantity of drug in a tree like structure


Massive amounts of drug can be delivered to a tumor cell
Massive Amounts of Drug can be Delivered to a Tumor Cell and a triggering enzyme.

The quantity can increase exponentially



Self amplifying exponential prtt

Self-Amplifying Exponential PRTT and a triggering enzyme.

The very binding of a male ligand and female adaptor creates two new female adaptors without the need for a triggering enzyme.


Unmasked Female Adaptor and a triggering enzyme.

Masked

Female Adaptor

Male

Adaptor

Male and Female

Covalently Bound

Masked

Female Adaptor

Unmasked

Female Adaptor

Unmasked

Female Adaptor


Masked Female Adaptor and a triggering enzyme.

Masked Female Adaptor

Bulky Group

Masked Male Adaptor


Unmasked Female Adaptor and a triggering enzyme.

Female Adaptor from

a second molecule

Bulky Group

Unmasked

Female Adaptor


Female adaptors can transform different patterns into a common target
Female Adaptors can Transform Different Patterns into a Common Target

This can enable the efficient delivery of multiple drugs to each target pattern and prevent the development of drug resistance.


A wide range of possibilities and emergent properties can arise with drugs that interact with each other.


Amplification and positive feedback can be achieved by delivering enzymes to adaptors which in turn unmask additional adaptors.


An other approach is to deliver a marker to the target patterns that make it look to the immune system like a bacterial infection.


Massive signal amplification is possible along with a change in scale.

To attract and activate one neutrophil requires only a small number ofchemotactic molecules.


Each neutrophil can deliver billions of molecules of
Each neutrophil can deliver in scale.billions of molecules of:

  • Hydrogen peroxide

  • Myeloperoxidase

  • MMP-9

  • Urokinase

  • Elastase

  • Catepsins


The system exhibits positive feedback
The system exhibits positive feedback: in scale.

  • Myeloperoxidase activates neutrophils

  • ROS inactivate protease inhibitors

  • Ros activate MMP’s

  • Ros stimulate MMP production

  • Cathepsins

The protease released can also activate MMP-2, MMP-9, and plasminogen.


The net result could be a massive signal amplification in and around the target pattern and… a change in scale.


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