the sum of its parts? antibody-drug conjugates (adcs): can an adc be greater than

the sum of its parts?

Antibody-drug conjugates (ADCs):Can an ADC be greater than

2

This educational program is prepared by

F. Hoffmann-La Roche Ltd

The purpose of this educational program is to provide an overview of an investigational mechanism of action and should not be

construed as a recommendation for use of any product for unapproved uses. Products under investigational study have not been approved

by any Health Authority for the use outside clinical trial setting.

This educational program may be implemented only upon receipt of local jurisdiction's

regulatory approval and following local affiliate legal/regulatory review.

Disclosure

Overview

• The definition of an ADC

• Components of an ADC

• Proposed mechanisms of action of ADCs

• Potential of ADCs

• Summary

3

What are antibody-drug conjugates (ADCs)?

• An ADC is a unique combination of1-4

– A targeted monoclonal antibody (mAb)

– A stable linker

– A potent cytotoxic agent

• ADCs are designed to selectively kill cancer cells while minimising effects on normal tissue1-4

4

1. Jaracz et al. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu et al. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart et al. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula et al. Nat Biotechnol. 2008;26:925-932.

Potent cytotoxic agent

Stable linker

mAb

Critical parameters for development of an ideal ADC

5

Potent cytotoxic agent

Stable linker

Targeted mAb

Each element of an ADCmust fulfill exacting criteria

Overview





• Summary

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mAbs are designed to target cancer cells and may possess their own anticancer effects

• Preclinical studies show that mAbs integrated into an ADC should1-5

– Target antigens that are preferentially or exclusively expressed on the surface of cancer cells

– Display a high binding affinity and high selectivity to the antigen

– Persist in circulation to allow prolonged exposure of the cancer cells to the ADC4

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1. Jaracz et al. Bioorg Med Chem. 2005;13:5043-5054. 2. Oflazoglu et al. Clin Cancer Res. 2008;14:6171-6180. 3. Carter et al. Cancer J. 2008;14:154-169. 4. Chari. Acc Chem Res. 2008;41:98-107. 5. Ricart et al. Nat Clin Pract Oncol. 2007;4:245-255.

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mAbs are designed to target cancer cells and may possess their own anticancer effects

• mAb-mediated anticancer activities may include1-3:

– Prevention of signaling

– Ability to initiate a cytotoxic immune response by effector cells (eg, antibody-dependent cellular cytotoxicity [ADCC])

– Induction of apoptosis

• mAbs may retain these activities when integrated into an ADC1,2

1. Oflazoglu et al. Clin Cancer Res. 2008;14:6171-6180. 2. Carter et al. Cancer J. 2008;14:154-169. 3. Ricart et al. Nat Clin Pract Oncol. 2007;4:245-255.

mAbs may be developed to target a variety of cancers

*This is not a comprehensive list of antigen targets under investigation in ADCs.

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Target antigen* Cancer type

CanAg1-4 Gastric cancer, solid tumours

CD191,4,5 Non-Hodgkin’s lymphoma (NHL)

CD204 B-cell malignancies

CD221,4,6 NHL

CD301,4,7-9 CD30+ malignancies, Hodgkin lymphoma, anaplastic large cell lymphoma

CD561,4,10 Multiple myeloma, solid tumours

CD79b4,11 NHL

EphA24,12 Solid tumours

HER21,4 HER2-positive breast cancer

Lewis Y1,4,13 Epithelial cancers

1. Carter et al. Cancer J. 2008;14:154-169. 2. Erickson et al. Cancer Res. 2006;66:4426-4433. 3. Widdison et al. J Med Chem. 2006;49:4392-4408. 4. Teicher. Curr Cancer Drug Targets. 2009;9:982-1004. 5. Gerber et al. Blood. 2009;113:4352-4361. 6. DiJoseph et al. Clin Cancer Res. 2004;10:8620-8629. 7. Oflazoglu et al. Br J Haematol. 2008;142:69-73. 8. Ansell et al. J Clin Oncol. 2007;25:2764-2769. 9. Bartlett et al. Blood. 2008;111:1848-1854. 10. Tassone et al. Cancer Res. 2004;64:4629-4636. 11. Dornan et al. Blood. 2009;114:2721-2729. 12. Jackson et al. Cancer Res. 2008;68:9367-9374. 13. Herbertson et al. Clin Cancer Res. 2009;15:6709-6715.

Stable linkers are designed to prevent the release of the cytotoxic agent into the circulation1-4

• Preclinical studies suggest that selection of a linker depends on4

– Cancer type and the cytotoxic agent in use

– Stability in circulation

– Ability to be efficiently cleaved within cancer cells

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1. Jaracz et al. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu et al. Nat Biotechnol. 2005;23:1137-1146. 3. Chari. Acc Chem Res. 2008;41:98-107. 4. Sanderson et al. Clin Cancer Res. 2005;11:843-852.

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Current linkers under investigation in ADCs

1. Carter et al. Cancer J. 2008;14:154-169. 2. Sanderson et al. Clin Cancer Res. 2005;11:843-852. 3. Chari. Acc Chem Res. 2008;41:98-107. 4. Oflazoglu et al. Clin Cancer Res. 2008;14:6171-6180.

Linker Release mechanism

Hydrazone Designed for serum stability and degradation in acidic compartments within the cytoplasm1

Peptide Designed to be enzymatically hydrolysed by lysosomal proteases such as cathepsin B1,2

Disulfide Designed to be cleaved through disulfide exchange with an intracellular thiol, such as glutathione1,3

Thioether Nonreducible and designed for intracellular proteolytic degradation1,4

Potent cytotoxic agent: Killing cancer cells from within

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1. Chari. Acc Chem Res. 2008;41:98-107. 2. Ricart et al. Nat Clin Pract Oncol. 2007;4:245-255. 3. Hamann. Expert Opin Ther Patents. 2005;15:1087-1103. 4. Oflazoglu et al. Br J Haematol. 2008;142:69-73.

• Based on preclinical models, criteria for ideal cytotoxic agents include1-4:

– High potency in vitro

– Sensitivity of the cancer type to the cytotoxic agent

– Potential to induce cell death from within the cancer cell

– Must be stable while bound to antibody3

• Cannot lose potency while in the blood

• Cannot be deactivated by lysosomal proteolysis, hydrolysis, or acidity

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Cytotoxic agents investigated for ADCs may be up to 1000-fold more potent than agents initially investigated1-3

1. Chari. Acc Chem Res. 2008;41:98-107. 2. Wu et al. Nat Biotechnol. 2005;23:1137-1146. 3. Carter et al. Cancer J. 2008;14:154-169. 4. Minotti et al. Pharmacol Rev. 2004;56:185-229. 5. Ricart et al. Nat Clin Pract Oncol. 2007;4:245-255.

Name Target Mode of action

Doxorubicin derivatives4

Topoisomerase II DNA complexes

Inhibit DNA religation, leading to DNA double-strand breaks

Maytansinoids5 α-tubulin Prevent tubulin polymerisation

Auristatins5 α-tubulin Prevent tubulin polymerisation

Calicheamicin5 Sequence-specific minor groove of DNA

Causes double-strand DNA breaks

CC-10651 Sequence-specific minor groove of DNA

Induces adenine alkylation

Overview





• Summary

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Proposed mechanisms of action of ADCs:Binding to the target antigen

• Based on preclinical models

• The ADC binds to the target antigen on the cell surface1,2

• Proposed mechanisms ofaction of this binding mayinclude mAb-mediatedanticancer effects, such as prevention of signaling, ADCC, and induction of apoptosis3-5

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1. Jaracz et al. Bioorg Med Chem. 2005;13:5043-5054. 2. Chari. Acc Chem Res. 2008;41:98-107. 3. Ricart et al. Nat Clin Pract Oncol. 2007;4:245-255. 4. Carter et al. Cancer J. 2008;14:154-169. 5. Oflazoglu et al. Clin Cancer Res. 2008;14:6171-6180.

Proposed mechanisms of action of ADCs:Endocytosis


• Upon binding to the target antigen, theADC-antigen complex is internalised1,2

• This initial process may berequired for activation of the ADC3

161. Jaracz et al. Bioorg Med Chem. 2005;13:5043-5054. 2. Chari. Acc Chem Res. 2008;41:98-107. 3. Erickson et al. Cancer Res. 2006;66:4426-4433.

Proposed mechanisms of action of ADCs:Lysosomal degradation


• Internalisation of the ADC antigen complex into endosomes is followed by delivery of the complex to the lysosomal compartment1

• The lysosomes are both acidic and rich in proteolytic enzymes2

171. Erickson et al. Cancer Res. 2006;66:4426-4433. 2. Carter et al. Cancer J. 2008;14:154-169.

Proposed mechanisms of action of ADCs:Cell death


• This lysosomal degradation results in release of the cytotoxic agent1

• The cytotoxic agent then interacts with critical cellular machinery to elicit cell death2

181. Carter et al. Cancer J. 2008;14:154-169. 2. Alley et al. J Pharmacol Exp Ther. 2009;330:932-938.

Proposed mechanisms of action of ADCs

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Overview



• Proposed mechanisms of action

of ADCs


• Summary

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Potential of ADCs: Targeting an unmet need

• Despite recent oncology breakthroughs, conventional anticancer treatments may have limitations1,2

• These limitations highlight the need and provide the rationale for the development of ADCs

1. Jaracz et al. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu et al. Nat Biotechnol. 2005;23:1137-1146.

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Potential clinical application of ADCs in oncology

• Many cancers are known to either preferentially or exclusively express antigens that can be targeted1-3

• Potential methods for targeting these cancers with ADCs involve3

– Creating new mAbs specific for the preferentially expressed antigen and linking them with appropriate potent cytotoxic agents4

– Using active existing mAbs already in clinical use to deliver a potent cytotoxic agent that would be intolerable if administered alone2

1. Jaracz et al. Bioorg Med Chem. 2005;13:5043-5054. 2. Carter et al. Cancer J. 2008;14:154-169. 3. Junutula et al. Nat Biotechnol. 2008;26:925-932. 4. Kovtun et al. Cancer Lett. 2007;255:232-240.

Overview





• Summary

23

Summary

• ADCs are a unique combination of a targeted mAb, a stable linker, and a potent cytotoxic agent

• ADCs have multiple proposed mechanisms of action, including mAb mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic agent1-3

– mAbs are designed to target cancer cells and may possess their own anticancer effects1-5

– Stable linkers are designed to allow ADCs to remain inactive while in circulation1,4,6,7

– Potent cytotoxic agents kill cancer cells from within1,5,8,9

• Target antigen expression, selectivity of the mAb, linker stability, and potency of the cytotoxic agent are all key considerations when optimising and developing an ADC

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1. Chari. Acc Chem Res. 2008;41:98-107. 2. Carter et al. Cancer J. 2008;14:154-169. 3. Oflazoglu et al. Clin Cancer Res. 2008;14:6171-6180. 4. Jaracz et al. Bioorg Med Chem. 2005;13:5043-5054. 5. Ricart et al. Nat Clin Pract Oncol. 2007;4:245-255. 6. Wu et al. Nat Biotechnol. 2005;23:1137-1146. 7. Sanderson et al. Clin Cancer Res. 2005;11:843-852. 8. Hamann. Expert Opin Ther Patents. 2005;15:1087-1103. 9. Oflazoglu et al. Br J Haematol. 2008;142:69-73.

Suggested reading for further information on ADCs

• Bodey B, Bodey B Jr, Siegel SE, Kaiser HE. Genetically engineered monoclonal antibodies for direct anti-neoplastic treatment and cancer cell specific delivery of chemotherapeutic agents. Curr Pharm Des. 2000;6:261-276.

• Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169.

• Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107.

• Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66:4426-4433.

• Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054.

• Kovtun YV, Goldmacher VS. Cell killing by antibody-drug conjugates. Cancer Lett. 2007;255:232-240.

• Reichert JM, Valge-Archer VE. Development trends for monoclonal antibody cancer therapeutics. Nat Rev Drug Discov. 2007;6:349-356.

• Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255.

• Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146.

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APPENDIX

APPENDIX

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History of ADCs

1. Ghose et al. J Natl Cancer Inst. 1978;61:657-676. 2. Ranson et al. Oncology. 2002;63:17-24. 3. Ricart et al. Nat Clin Pract Oncol. 2007;4:245-255. 4. Jaracz et al. Bioorg Med Chem. 2005;13:5043-5054. 5. Carter et al. Cancer J. 2008;14:154-169.

1950s

• Research into ADCs begins1

1900s

• The concept of a targeted therapy to treat malignant diseases is conceived1

1970s/1980s

• Advances in antibody technology and intensive investigation of linkers to bind cytotoxic agents progress the development of ADCs2,3

2009 and beyond

• Decades of dedicated research have resulted in the capacity to create a new generation of ADCs1,5

2000

• The first ADC for clinical use in oncology becomes available (anti CD33)4

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the sum of its parts? antibody-drug conjugates (adcs): can an adc be greater than

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